БИОХИМИЯ, 2020, том 85, вып. 11, с. 1633–1675

УДК 577.12

Краткий справочник по низкомолекулярным ингибиторам эукариотической трансляции*

Обзор

© 2020 С.Е. Дмитриев 1,2,3**, Д.О. Владимиров 2, К.А. Лашкевич 1

НИИ физико-химической биологии имени А.Н. Белозерского, Московский государственный университет имени М.В. Ломоносова, 119234 Москва, Россия; электронная почта: sergey.dmitriev@belozersky.msu.ru

Московский государственный университет имени М.В. Ломоносова, факультет биоинженерии и биоинформатики, 119234 Москва, Россия

Институт молекулярной биологии имени В.А. Энгельгардта РАН, Москва, 119991 Россия

Поступила в редакцию 26.08.2020
После доработки 04.10.2020
Принята к публикации 04.10.2020

DOI: 10.31857/S0320972520110093

КЛЮЧЕВЫЕ СЛОВА: низкомолекулярные ингибиторы, рибосомные 40S и 60S субчастицы, 4E-BP1, фосфорилирование eIF2α, риботоксический стресс, циклогексимид, харрингтонин, трихотециновые микотоксины, аминогликозиды, рапамицин.

Аннотация

Эукариотическая рибосома и аппарат кеп-зависимой трансляции являются привлекательными мишенями для противо­опухолевой, антивирусной, противо­воспалительной и антипара­зитарной терапии. В настоящее время известен широкий спектр низкомолеку­лярных ингибиторов, специфично подавляющих биосинтез белка в клетках эукариот. Большое количество таких веществ обнаруживается среди хорошо изученных антибиотиков, чьё действие направлено на рибосому. Они включают ингибиторы транслокации и пептидил-трансферазного центра, блокаторы рибосомного пептидного туннеля, индукторы ошибок декоди­рования, преждевременной терминации и сквозного прочтения стоп-кодонов, а также модуляторы связывания компонентов трансляцион­ного аппарата с рибосомой. Отдельного внимания заслуживают низкомолеку­лярные ингибиторы аминоацил-тРНК-синтетаз, трансляционных факторов и сигнальных путей, ассоциированных с трансляцией, в том числе ингибиторы киназы mTOR. Рибосом-направленные ингибиторы широко применяются для анализа экспрессии генов методом рибосомного профайлинга, при селекции культиви­руемых клеток, используются в качестве фунгицидов в сельском хозяйстве и как противо­грибковые и анти­гельминтные средства в медицине. С веществами, влияющими на точность распознавания стоп-кодона, связаны надежды в терапии наследственных заболеваний, вызываемых нонсенс-мутациями, и восстановлении функции онкосупрессоров в опухолях. Некоторые ингибиторы биосинтеза белка обнаруживают также свойства геропротекторов. В данном обзоре мы приводим список как хорошо изученных, так и малоизвестных ингибиторов эукариотической трансляции (не касаясь биосинтеза белка в митохондриях и пластидах), дополненный информацией об их непосредст­венных мишенях и краткой характеристикой механизмов действия. Мы также представляем обновляемую базу данных, которая на данный момент содержит информацию о 370 ингибиторах. База данных размещена по адресу: http://eupsic.belozersky.msu.ru/.

Текст статьи

Пожалуйста, введите код, чтобы получить PDF файл с полным текстом статьи:

captcha

Сноски

* Статья на английском языке опубликована в режиме Open Access (открытого доступа) на сайте издательства Springer (https://link.springer.com/journal/10541), том 85, вып. 11, 2020.

** Адресат для корреспонденции.

Финансирование

Работа выполнена при финансовой поддержке Российского научного фонда (грант № 18-14-00291).

Благодарности

Авторы благодарят Максима Лашкевича за помощь в подготовке таблиц и администрацию компьютерного сервера НИИ ФХБ МГУ за помощь в размещении базы данных.

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания каких-либо исследований с участием людей или животных в качестве объектов.

Список литературы

1. Pelletier, J., and Sonenberg, N. (2019) The organizing principles of eukaryotic ribosome recruitment, Annu. Rev. Biochem., 88, 307-335, doi: 10.1146/annurev-biochem-013118-111042.

2. Yusupova, G., and Yusupov, M. (2014) High-resolution structure of the eukaryotic 80S ribosome, Annu. Rev. Biochem., 83, 467-486, doi: 10.1146/annurev-biochem-060713-035445.

3. Weisser, M., and Ban, N. (2019) Extensions, extra factors, and extreme complexity: ribosomal structures provide insights into eukaryotic translation, Cold Spring Harb. Perspect. Biol., 11, a032367, doi: 10.1101/cshperspect.a032367.

4. Andreev, D. E., O’Connor, P. B., Loughran, G., Dmitriev, S. E., Baranov, P. V., and Shatsky, I. N. (2017) Insights into the mechanisms of eukaryotic translation gained with ribosome profiling, Nucleic acids Res., 45, 513-526, doi: 10.1093/nar/gkw1190.

5. Hinnebusch, A. G. (2017) Structural insights into the mechanism of scanning and start codon recognition in eukaryotic translation initiation, Trends Biochem. Sci., 42, 589-611, doi: 10.1016/j.tibs.2017.03.004.

6. Schuller, A. P., and Green, R. (2018) Roadblocks and resolutions in eukaryotic translation, Nat. Rev. Mol. Cell Biol., 19, 526-541, doi: 10.1038/s41580-018-0011-4.

7. Wilson, D. N. (2009) The A-Z of bacterial translation inhibitors, Crit. Rev. Biochem. Mol. Biol., 44, 393-433, doi: 10.3109/10409230903307311.

8. Lin, J., Zhou, D., Steitz, T. A., Polikanov, Y. S., and Gagnon, M. G. (2018) Ribosome-targeting antibiotics: modes of action, mechanisms of resistance, and implications for drug design, Annu. Rev. Biochem., 87, 451-478, doi: 10.1146/annurev-biochem-062917-011942.

9. Yusupova, G., and Yusupov, M. (2017) Crystal structure of eukaryotic ribosome and its complexes with inhibitors, Philos. Trans. R. Soc. London B Biol. Sci., 372, 20160184, doi: 10.1098/rstb.2016.0184.

10. Vazquez, D. (1979) Inhibitors of protein biosynthesis, Mol. Biol. Biochem. Biophys., 30, 1-312, doi: 10.1007/978-3-642-81309-2.

11. Pestka, S. (1971) Inhibitors of ribosome functions, Annu. Rev. Microbiol., 25, 487-562, doi: 10.1146/annurev.mi.25.100171.002415.

12. Pestka, S. (1974) The use of inhibitors in studies on protein synthesis, Methods Enzymol., 30, 261-282, doi: 10.1016/0076-6879(74)30030-4.

13. Jiménez, A., and Vázquez, D. (1983) Novel Inhibitors of Translation in Eukaryotic Systems, in Modes and Mechanisms of Microbial Growth Inhibitors (Hahn, F. E. ed.), Springer Berlin Heidelberg, Berlin, Heidelberg, pp. 248-254.

14. Garreau de Loubresse, N., Prokhorova, I., Holtkamp, W., Rodnina, M. V., Yusupova, G., and Yusupov, M. (2014) Structural basis for the inhibition of the eukaryotic ribosome, Nature, 513, 517-522, doi: 10.1038/nature13737.

15. Barbacid, M., and Vazquez, D. (1974) (3H)anisomycin binding to eukaryotic ribosomes, J. Mol. Biol., 84, 603-623, doi: 10.1016/0022-2836(74)90119-3.

16. Wu, C. C., Zinshteyn, B., Wehner, K. A., and Green, R. (2019) High-resolution ribosome profiling defines discrete ribosome elongation states and translational regulation during cellular stress, Mol. Cell, 73, 959-970 e955, doi: 10.1016/j.molcel.2018.12.009.

17. Barbacid, M., Fresno, M., and Vazquez, D. (1975) Inhibitors of polypeptide elongation on yeast polysomes, J. Antibiot. (Tokyo), 28, 453-462, doi: 10.7164/antibiotics.28.453.

18. Fresno, M., Carrasco, L., and Vazquez, D. (1976) Initiation of the polypeptide chain by reticulocyte cell-free systems. Survey of different inhibitors of translation, Eur. J. Biochem., 68, 355-364, doi: 10.1111/j.1432-1033.1976.tb10822.x.

19. Cundliffe, E., Cannon, M., and Davies, J. (1974) Mechanism of inhibition of eukaryotic protein synthesis by trichothecene fungal toxins, Proc. Natl. Acad. Sci. USA, 71, 30-34, doi: 10.1073/pnas.71.1.30.

20. Pellegrino, S., Meyer, M., Zorbas, C., Bouchta, S. A., Saraf, K., Pelly, S. C., Yusupova, G., Evidente, A., Mathieu, V., Kornienko, A., Lafontaine, D. L. J., and Yusupov, M. (2018) The amaryllidaceae alkaloid haemanthamine binds the eukaryotic ribosome to repress cancer cell growth, Structure, 26, 416-425 e414, doi: 10.1016/j.str.2018.01.009.

21. Baez, A., and Vazquez, D. (1978) Binding of [3H]narciclasine to eukaryotic ribosomes. A study on a structure-activity relationship, Biochim. Biophys. Acta, 518, 95-103, doi: 10.1016/0005-2787(78)90119-3.

22. Jimenez, A., Santos, A., Alonso, G., and Vazquez, D. (1976) Inhibitors of protein synthesis in eukarytic cells. Comparative effects of some amaryllidaceae alkaloids, Biochim. Biophys. Acta, 425, 342-348, doi: 10.1016/0005-2787(76)90261-6.

23. Fresno, M., Jimenez, A., and Vazquez, D. (1977) Inhibition of translation in eukaryotic systems by harringtonine, Eur. J. Biochem., 72, 323-330, doi: 10.1111/j.1432-1033.1977.tb11256.x.

24. Ingolia, N. T., Lareau, L. F., and Weissman, J. S. (2011) Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes, Cell, 147, 789-802, doi: 10.1016/j.cell.2011.10.002.

25. Tscherne, J. S., and Pestka, S. (1975) Inhibition of protein synthesis in intact HeLa cells, Antimicrob. Agents Chemother., 8, 479-487, doi: 10.1128/aac.8.4.479.

26. Gurel, G., Blaha, G., Moore, P. B., and Steitz, T. A. (2009) U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome, J. Mol. Biol., 389, 146-156, doi: 10.1016/j.jmb.2009.04.005.

27. Winer, E. S., and DeAngelo, D. J. (2018) A review of omacetaxine: a chronic myeloid leukemia treatment resurrected, Oncol. Ther., 6, 9-20, doi: 10.1007/s40487-018-0058-6.

28. Wang, Z., and Yang, L. (2020) Turning the tide: natural products and natural-product-inspired chemicals as potential counters to SARS-CoV-2 infection, Front. Pharmacol., 11, 1013, doi: 10.3389/fphar.2020.01013.

29. Huang, M. T. (1975) Harringtonine, an inhibitor of initiation of protein biosynthesis, Mol. Pharmacol., 11, 511-519.

30. Carter, C. J., and Cannon, M. (1977) Structural requirements for the inhibitory action of 12,13-epoxytrichothecenes on protein synthesis in eukaryotes, Biochem. J., 166, 399-409, doi: 10.1042/bj1660399.

31. Cannon, M., Jimenez, A., and Vazquez, D. (1976) Competition between trichodermin and several other sesquiterpene antibiotics for binding to their receptor site(s) on eukaryotic ribosomes, Biochem. J., 160, 137-145, doi: 10.1042/bj1600137.

32. Ehrlich, K. C., and Daigle, K. W. (1987) Protein synthesis inhibition by 8-oxo-12,13-epoxytrichothecenes, Biochim. Biophys. Acta, 923, 206-213, doi: 10.1016/0304-4165(87)90005-5.

33. Carter, C. J., and Cannon, M. (1978) Inhibition of eukaryotic ribosomal function by the sesquiterpenoid antibiotic fusarenon-X, Eur. J. Biochem., 84, 103-111, doi: 10.1111/j.1432-1033.1978.tb12146.x.

34. Schneider-Poetsch, T., Ju, J., Eyler, D. E., Dang, Y., Bhat, S., Merrick, W. C., Green, R., Shen, B., and Liu, J. O. (2010) Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin, Nat. Chem. Biol., 6, 209-217, doi: 10.1038/nchembio.304.

35. Chan, J., Khan, S. N., Harvey, I., Merrick, W., and Pelletier, J. (2004) Eukaryotic protein synthesis inhibitors identified by comparison of cytotoxicity profiles, RNA, 10, 528-543, doi: 10.1261/rna.5200204.

36. McClary, B., Zinshteyn, B., Meyer, M., Jouanneau, M., Pellegrino, S., Yusupova, G., Schuller, A., Reyes, J. C. P., Lu, J., Guo, Z., Ayinde, S., Luo, C., Dang, Y., Romo, D., Yusupov, M., Green, R., and Liu, J. O. (2017) Inhibition of eukaryotic translation by the antitumor natural product agelastatin A, Cell Chem. Biol., 24, 605-613 e605, doi: 10.1016/j.chembiol.2017.04.006.

37. Cuendet, M., and Pezzuto, J. M. (2004) Antitumor activity of bruceantin: an old drug with new promise, J. Nat. Prod., 67, 269-272, doi: 10.1021/np030304+.

38. Fresno, M., Gonzales, A., Vazquez, D., and Jimenez, A. (1978) Bruceantin, a novel inhibitor of peptide bond formation, Biochim. Biophys. Acta, 518, 104-112, doi: 10.1016/0005-2787(78)90120-x.

39. Zhang, L. L., Guo, J., Jiang, X. M., Chen, X. P., Wang, Y. T., Li, A., Lin, L. G., Li, H., and Lu, J. J. (2020) Identifica-tion of nagilactone E as a protein synthesis inhibitor with anticancer activity, Acta pharmacol. Sin., 41, 698-705, doi: 10.1038/s41401-019-0332-7.

40. Polikanov, Y. S., Starosta, A. L., Juette, M. F., Altman, R. B., Terry, D. S., Lu, W., Burnett, B. J., Dinos, G., Reynolds, K. A., Blanchard, S. C., Steitz, T. A., and Wilson, D. N. (2015) Distinct tRNA accommodation intermediates observed on the ribosome with the antibiotics hygromycin A and A201A, Mol. Cell, 58, 832-844, doi: 10.1016/j.molcel.2015.04.014.

41. Amunts, A., Fiedorczuk, K., Truong, T. T., Chandler, J., Greenberg, E. P., and Ramakrishnan, V. (2015) Bactobolin A binds to a site on the 70S ribosome distinct from previously seen antibiotics, J. Mol. Biol., 427, 753-755, doi: 10.1016/j.jmb.2014.12.018.

42. Hori, M., Suzukake, K., Ishikawa, C., Asakura, H., and Umezawa, H. (1981) Biochemical studies on bactobolin in relation to actinobolin, J. Antibiot. (Tokyo), 34, 465-468, doi: 10.7164/antibiotics.34.465.

43. Cerna, J., Rychlik, I., and Lichtenthaler, F. W. (1973) The effect of the aminoacyl-4-aminohexosyl-cytosine group of antibiotics on ribosomal peptidyl transferase, FEBS Lett., 30, 147-150, doi: 10.1016/0014-5793(73)80639-8.

44. Hansen, J. L., Moore, P. B., and Steitz, T. A. (2003) Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit, J. Mol. Biol., 330, 1061-1075, doi: 10.1016/s0022-2836(03)00668-5.

45. Svidritskiy, E., Ling, C., Ermolenko, D. N., and Korostelev, A. A. (2013) Blasticidin S inhibits translation by trapping deformed tRNA on the ribosome, Proc. Natl. Acad. Sci. USA, 110, 12283-12288, doi: 10.1073/pnas.1304922110.

46. Lashkevich, K. A., Shlyk, V. I., Kushchenko, A. S., Gladyshev, V. N., Alkalaeva, E. Z., and Dmitriev, S. E. (2020) CTELS: a cell-free system for the analysis of translation termination rate, Biomolecules, 10, 911, doi: 10.3390/biom10060911.

47. Gonzalez, A., Vazquez, D., and Jimenez, A. (1979) Inhibition of translation in bacterial and eukaryotic systems by the antibiotic anthelmycin (hikizimycin), Biochim. Biophys. Acta, 561, 403-409, doi: 10.1016/0005-2787(79)90148-5.

48. Sikorski, M. M., Cerna, J., Rychlik, I., and Legocki, A. B. (1977) Peptidyl transferase activity in wheat germ ribosomes. Effect of some antibiotics, Biochim. Biophys. Acta, 475, 123-130, doi: 10.1016/0005-2787(77)90346-x.

49. Leviev, I. G., Rodriguez-Fonseca, C., Phan, H., Garrett, R. A., Heilek, G., Noller, H. F., and Mankin, A. S. (1994) A conserved secondary structural motif in 23S rRNA defines the site of interaction of amicetin, a universal inhibitor of peptide bond formation, EMBO J., 13, 1682-1686.

50. Dmitriev, S. E., Akulich, K. A., Andreev, D. E., Terenin, I. M., and Shatsky, I. N. (2013) The peculiar mode of translation elongation inhibition by antitumor drug harringtonin, FEBS J., 280, 51-51.

51. Akulich, K. A., Sinitcyn, P. G., Lomakin, I. B., Andreev, D. E., Terenin, I. M., Smirnova, V. V., Mironov, A. A., Shatsky, I. N., and Dmitriev, S. E. (2017) Peptidyl transferase inhibitors arrest the ribosome at specific amino acid codons: insights from an integrated approach, FEBS J., 284, 296-296, doi: 10.1111/febs.14174.

52. Michel, A. M., Andreev, D. E., and Baranov, P. V. (2014) Computational approach for calculating the probability of eukaryotic translation initiation from ribo-seq data that takes into account leaky scanning, BMC Bioinform., 15, 380, doi: 10.1186/s12859-014-0380-4.

53. Marks, J., Kannan, K., Roncase, E. J., Klepacki, D., Kefi, A., Orelle, C., Vazquez-Laslop, N., and Mankin, A. S. (2016) Context-specific inhibition of translation by ribosomal antibiotics targeting the peptidyl transferase center, Proc. Natl. Acad. Sci. USA, 113, 12150-12155, doi: 10.1073/pnas.1613055113.

54. Vazquez-Laslop, N., and Mankin, A. S. (2018) Context-specific action of ribosomal antibiotics, Ann. Rev. Microbiol., 72, 185-207, doi: 10.1146/annurev-micro-090817-062329.

55. Kannan, K., Kanabar, P., Schryer, D., Florin, T., Oh, E., Bahroos, N., Tenson, T., Weissman, J. S., and Mankin, A. S. (2014) The general mode of translation inhibition by macrolide antibiotics, Proc. Natl. Acad. Sci. USA, 111, 15958-15963, doi: 10.1073/pnas.1417334111.

56. Mankin, A. S. (2008) Macrolide myths, Curr. Opin. Microbiol., 11, 414-421, doi: 10.1016/j.mib.2008.08.003.

57. Vazquez-Laslop, N., Thum, C., and Mankin, A. S. (2008) Molecular mechanism of drug-dependent ribosome stalling, Mol. Cell, 30, 190-202, doi: 10.1016/j.molcel.2008.02.026.

58. Tu, D., Blaha, G., Moore, P. B., and Steitz, T. A. (2005) Structures of MLSBK antibiotics bound to mutated large ribosomal subunits provide a structural explanation for resistance, Cell, 121, 257-270, doi: 10.1016/j.cell.2005.02.005.

59. Hansen, J. L., Ippolito, J. A., Ban, N., Nissen, P., Moore, P. B., and Steitz, T. A. (2002) The structures of four macrolide antibiotics bound to the large ribosomal subunit, Mol. Cell, 10, 117-128, doi: 10.1016/s1097-2765(02)00570-1.

60. Gurel, G., Blaha, G., Steitz, T. A., and Moore, P. B. (2009) Structures of triacetyloleandomycin and mycalamide A bind to the large ribosomal subunit of Haloarcula marismortui, Antimicrob. Agents Chemother., 53, 5010-5014, doi: 10.1128/AAC.00817-09.

61. Nishimura, S., Matsunaga, S., Yoshida, M., Hirota, H., Yokoyama, S., and Fusetani, N. (2005) 13-Deoxyteda-nolide, a marine sponge-derived antitumor macrolide, binds to the 60S large ribosomal subunit, Bioorg. Med. Chem., 13, 449-454, doi: 10.1016/j.bmc.2004.10.012.

62. Lintner, N. G., McClure, K. F., Petersen, D., Londregan, A. T., Piotrowski, D. W., Wei, L., Xiao, J., Bolt, M., Loria, P. M., Maguire, B., Geoghegan, K. F., Huang, A., Rolph, T., Liras, S., Doudna, J. A., Dullea, R. G., and Cate, J. H. (2017) Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain, PLoS Biol., 15, e2001882, doi: 10.1371/journal.pbio.2001882.

63. Liaud, N., Horlbeck, M. A., Gilbert, L. A., Gjoni, K., Weissman, J. S., and Cate, J. H. D. (2019) Cellular response to small molecules that selectively stall protein synthesis by the ribosome, PLoS Genet., 15, e1008057, doi: 10.1371/journal.pgen.1008057.

64. Li, W., Ward, F. R., McClure, K. F., Chang, S. T., Montabana, E., Liras, S., Dullea, R. G., and Cate, J. H. D. (2019) Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule, Nat. Struct. Mol. Biol., 26, 501-509, doi: 10.1038/s41594-019-0236-8.

65. Osterman, I. A., Wieland, M., Maviza, T. P., Lashkevich, K. A., Lukianov, D. A., Komarova, E. S., Zakalyukina, Y. V., Buschauer, R., Shiriaev, D. I., Leyn, S. A., Zlamal, J. E., Biryukov, M. V., Skvortsov, D. A., Tashlitsky, V. N., Polshakov, V. I., Cheng, J., Polikanov, Y. S., Bogdanov, A. A., Osterman, A. L., Dmitriev, S. E., Beckmann, R., Dontsova, O. A., Wilson, D. N., and Sergiev, P. V. (2020) Tetracenomycin X inhibits translation by binding within the ribosomal exit tunnel, Nat. Chem. Biol., 16, 1071-1077, doi: 10.1038/s41589-020-0578-x.

66. Mortison, J. D., Schenone, M., Myers, J. A., Zhang, Z., Chen, L., Ciarlo, C., Comer, E., Natchiar, S. K., Carr, S. A., Klaholz, B. P., and Myers, A. G. (2018) Tetracyclines modify translation by targeting key human rRNA substructures, Cell Chem. Biol., 25, 1506-1518 e1513, doi: 10.1016/j.chembiol.2018.09.010.

67. Wu, C. C., Peterson, A., Zinshteyn, B., Regot, S., and Green, R. (2020) Ribosome collisions trigger general stress responses to regulate cell fate, Cell, 182, 404-416 e414, doi: 10.1016/j.cell.2020.06.006.

68. Jenner, L., Starosta, A. L., Terry, D. S., Mikolajka, A., Filonava, L., Yusupov, M., Blanchard, S. C., Wilson, D. N., and Yusupova, G. (2013) Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis, Proc. Natl. Acad. Sci. USA, 110, 3812-3816, doi: 10.1073/pnas.1216691110.

69. Solis, G. M., Kardakaris, R., Valentine, E. R., Bar-Peled, L., Chen, A. L., Blewett, M. M., McCormick, M. A., Williamson, J. R., Kennedy, B., Cravatt, B. F., and Petrascheck, M. (2018) Translation attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms, eLife, 7, doi: 10.7554/eLife.40314.

70. Garrido-Mesa, N., Zarzuelo, A., and Galvez, J. (2013) Minocycline: far beyond an antibiotic, Br. J. Pharmacol., 169, 337-352, doi: 10.1111/bph.12139.

71. Obrig, T. G., Culp, W. J., McKeehan, W. L., and Hardesty, B. (1971) The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes, J. Biol. Chem., 246, 174-181.

72. Klinge, S., Voigts-Hoffmann, F., Leibundgut, M., Arpagaus, S., and Ban, N. (2011) Crystal structure of the eukaryotic 60S ribosomal subunit in complex with initiation factor 6, Science, 334, 941-948, doi: 10.1126/science.1211204.

73. Dmitriev, S. E., Pisarev, A. V., Rubtsova, M. P., Dunaevsky, Y. E., and Shatsky, I. N. (2003) Conversion of 48S translation preinitiation complexes into 80S initiation complexes as revealed by toeprinting, FEBS Lett., 533, 99-104, doi: 10.1016/s0014-5793(02)03776-6.

74. Budkevich, T., Giesebrecht, J., Altman, R. B., Munro, J. B., Mielke, T., Nierhaus, K. H., Blanchard, S. C., and Spahn, C. M. (2011) Structure and dynamics of the mammalian ribosomal pretranslocation complex, Mol. Cell, 44, 214-224, doi: 10.1016/j.molcel.2011.07.040.

75. Myasnikov, A. G., Kundhavai Natchiar, S., Nebout, M., Hazemann, I., Imbert, V., Khatter, H., Peyron, J. F., and Klaholz, B. P. (2016) Structure-function insights reveal the human ribosome as a cancer target for antibiotics, Nat. Commun., 7, 12856, doi: 10.1038/ncomms12856.

76. Pestova, T. V., and Hellen, C. U. (2003) Translation elongation after assembly of ribosomes on the Cricket paralysis virus internal ribosomal entry site without initiation factors or initiator tRNA, Gen. Dev., 17, 181-186, doi: 10.1101/gad.1040803.

77. Iwasaki, S., and Ingolia, N. T. (2017) The growing toolbox for protein synthesis studies, Trends Biochem. Sci., 42, 612-624, doi: 10.1016/j.tibs.2017.05.004.

78. Park, Y., Koga, Y., Su, C., Waterbury, A. L., Johnny, C. L., and Liau, B. B. (2019) Versatile synthetic route to cycloheximide and analogues that potently inhibit translation elongation, Angew. Chem. Int. Ed. Engl., 58, 5387-5391, doi: 10.1002/anie.201901386.

79. Landsman, D., Srikantha, T., and Bustin, M. (1988) Single copy gene for the chicken non-histone chromosomal protein HMG-17, J. Biol. Chem., 263, 3917-3923.

80. Zhang, D., Yi, W., Ge, H., Zhang, Z., and Wu, B. (2019) Bioactive streptoglutarimides A-J from the marine-derived Streptomyces sp. ZZ741, J. Nat. Prod., 82, 2800-2808, doi: 10.1021/acs.jnatprod.9b00481.

81. Sugawara, K., Nishiyama, Y., Toda, S., Komiyama, N., Hatori, M., Moriyama, T., Sawada, Y., Kamei, H., Konishi, M., and Oki, T. (1992) Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity, J. Antibiot. (Tokyo), 45, 1433-1441, doi: 10.7164/antibiotics.45.1433.

82. Lee, S., Liu, B., Lee, S., Huang, S. X., Shen, B., and Qian, S. B. (2012) Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution, Proc. Natl. Acad. Sci. USA, 109, E2424-2432, doi: 10.1073/pnas.1207846109.

83. Pellegrino, S., Meyer, M., Konst, Z. A., Holm, M., Voora, V. K., Kashinskaya, D., Zanette, C., Mobley, D. L., Yusupova, G., Vanderwal, C. D., Blanchard, S. C., and Yusupov, M. (2019) Understanding the role of intermolecular interactions between lissoclimides and the eukaryotic ribosome, Nucleic Acids Res., 47, 3223-3232, doi: 10.1093/nar/gkz053.

84. Konst, Z. A., Szklarski, A. R., Pellegrino, S., Michalak, S. E., Meyer, M., Zanette, C., Cencic, R., Nam, S., Voora, V. K., Horne, D. A., Pelletier, J., Mobley, D. L., Yusupova, G., Yusupov, M., and Vanderwal, C. D. (2017) Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides, Nat. Chem., 9, 1140-1149, doi: 10.1038/nchem.2800.

85. Robert, F., Gao, H. Q., Donia, M., Merrick, W. C., Hamann, M. T., and Pelletier, J. (2006) Chlorolis-soclimides: new inhibitors of eukaryotic protein synthesis, RNA, 12, 717-725, doi: 10.1261/rna.2346806.

86. Lee, K. H., Nishimura, S., Matsunaga, S., Fusetani, N., Horinouchi, S., and Yoshida, M. (2005) Inhibition of protein synthesis and activation of stress-activated protein kinases by onnamide A and theopederin B, antitumor marine natural products, Cancer Sci., 96, 357-364, doi: 10.1111/j.1349-7006.2005.00055.x.

87. Brega, A., Falaschi, A., De Carli, L., and Pavan, M. (1968) Studies on the mechanism of action of pederine, J. Cell Biol., 36, 485-496, doi: 10.1083/jcb.36.3.485.

88. Jacobs-Lorena, M., Brega, A., and Baglioni, C. (1971) Inhi-bition of protein synthesis in reticulocytes by antibiotics. V. Mechanism of action of pederine, an inhibitor of initiation and elongation, Biochim. Biophys. Acta, 240, 263-272.

89. Schroeder, S. J., Blaha, G., Tirado-Rives, J., Steitz, T. A., and Moore, P. B. (2007) The structures of antibiotics bound to the E site region of the 50 S ribosomal subunit of Haloarcula marismortui: 13-deoxytedanolide and girodazole, J. Mol. Biol., 367, 1471-1479, doi: 10.1016/j.jmb.2007.01.081.

90. Taylor, R. E. (2008) Tedanolide and the evolution of polyketide inhibitors of eukaryotic protein synthesis, Nat. Prod. Rep., 25, 854-861, doi: 10.1039/b805700c.

91. Hines, J., Roy, M., Cheng, H., Agapakis, C. M., Taylor, R., and Crews, C. M. (2006) Myriaporone 3/4 structure—activity relationship studies define a pharmacophore targeting eukaryotic protein synthesis, Mol. Biosyst., 2, 371-379, doi: 10.1039/b602936a.

92. Muthukumar, Y., Roy, M., Raja, A., Taylor, R. E., and Sasse, F. (2013) The marine polyketide myriaporone 3/4 stalls translation by targeting the elongation phase, Chembiochem, 14, 260-264, doi: 10.1002/cbic.201200522.

93. Prokhorova, I. V., Akulich, K. A., Makeeva, D. S., Osterman, I. A., Skvortsov, D. A., Sergiev, P. V., Dontsova, O. A., Yusupova, G., Yusupov, M. M., and Dmitriev, S. E. (2016) Amicoumacin A induces cancer cell death by targeting the eukaryotic ribosome, Sci. Rep., 6, 27720, doi: 10.1038/srep27720.

94. Wong, W., Bai, X. C., Brown, A., Fernandez, I. S., Hanssen, E., Condron, M., Tan, Y. H., Baum, J., and Scheres, S. H. (2014) Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine, eLife, 3, doi: 10.7554/eLife.03080.

95. Chang, S., and Wasmuth, J. J. (1983) Construction and characterization of Chinese hamster cell EmtA EmtB double mutants, Mol. Cell. Biol., 3, 761-772, doi: 10.1128/mcb.3.5.761.

96. Grant, P., Sanchez, L., and Jimenez, A. (1974) Cryptopleurine resistance: genetic locus for a 40S ribosomal component in Saccharomyces cerevisiae, J. Bacteriol., 120, 1308-1314, doi: 10.1128/JB.120.3.1308-1314.1974.

97. Gupta, R. S., and Siminovitch, L. (1977) Mutants of CHO cells resistant to the protein synthesis inhibitors, cryptopleurine and tylocrebrine: genetic and biochemical evidence for common site of action of emetine, cryptopleurine, tylocrebine, and tubulosine, Biochemistry, 16, 3209-3214, doi: 10.1021/bi00633a026.

98. Bucher, K., and Skogerson, L. (1976) Cryptopleurine—an inhibitor of translocation, Biochemistry, 15, 4755-4759, doi: 10.1021/bi00667a001.

99. Carrasco, L., Jimenez, A., and Vazquez, D. (1976) Specific inhibition of translocation by tubulosine in eukaryotic polysomes, Eur. J. Biochem., 64, 1-5, doi: 10.1111/j.1432-1033.1976.tb10268.x.

100. Wang, Y., Wong, H. C., Gullen, E. A., Lam, W., Yang, X., Shi, Q., Lee, K. H., and Cheng, Y. C. (2012) Cryptopleurine analogs with modification of e ring exhibit different mechanism to rac-cryptopleurine and tylophorine, PloS One, 7, e51138, doi: 10.1371/journal.pone.0051138.

101. Donaldson, G. R., Atkinson, M. R., and Murray, A. W. (1968) Inhibition of protein synthesis in Ehrlich ascites-tumour cells by the phenanthrene alkaloids tylophorine, tylocrebrine and cryptopleurine, Biochem. Biophys. Res. Commun., 31, 104-109, doi: 10.1016/0006-291x(68)90037-5.

102. Polikanov, Y. S., Osterman, I. A., Szal, T., Tashlitsky, V. N., Serebryakova, M. V., Kusochek, P., Bulkley, D., Malanicheva, I. A., Efimenko, T. A., Efremenkova, O. V., Konevega, A. L., Shaw, K. J., Bogdanov, A. A., Rodnina, M. V., Dontsova, O. A., Mankin, A. S., Steitz, T. A., and Sergiev, P. V. (2014) Amicoumacin a inhibits translation by stabilizing mRNA interaction with the ribosome, Mol. Cell, 56, 531-540, doi: 10.1016/j.molcel.2014.09.020.

103. Brodersen, D. E., Clemons, W. M., Jr., Carter, A. P., Morgan-Warren, R. J., Wimberly, B. T., and Ramakrishnan, V. (2000) The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit, Cell, 103, 1143-1154, doi: 10.1016/s0092-8674(00)00216-6.

104. Dinos, G., Wilson, D. N., Teraoka, Y., Szaflarski, W., Fucini, P., Kalpaxis, D., and Nierhaus, K. H. (2004) Dissecting the ribosomal inhibition mechanisms of edeine and pactamycin: the universally conserved residues G693 and C795 regulate P-site RNA binding, Mol. Cell, 13, 113-124, doi: 10.1016/s1097-2765(04)00002-4.

105. Borovinskaya, M. A., Shoji, S., Fredrick, K., and Cate, J. H. (2008) Structural basis for hygromycin B inhibition of protein biosynthesis, RNA, 14, 1590-1599, doi: 10.1261/rna.1076908.

106. Gonzalez, A., Jimenez, A., Vazquez, D., Davies, J. E., and Schindler, D. (1978) Studies on the mode of action of hygromycin B, an inhibitor of translocation in eukaryotes, Biochim. Biophys. Acta, 521, 459-469, doi: 10.1016/0005-2787(78)90287-3.

107. Misumi, M., Nishimura, T., Komai, T., and Tanaka, N. (1978) Interaction of kanamycin and related antibiotics with the large subunit of ribosomes and the inhibition of translocation, Biochem. Biophys. Res. Commun., 84, 358-365, doi: 10.1016/0006-291x(78)90178-x.

108. Cabanas, M. J., Vazquez, D., and Modolell, J. (1978) Inhibition of ribosomal translocation by aminoglycoside antibiotics, Biochem. Biophys. Res. Commun., 83, 991-997, doi: 10.1016/0006-291x(78)91493-6.

109. Borovinskaya, M. A., Pai, R. D., Zhang, W., Schuwirth, B. S., Holton, J. M., Hirokawa, G., Kaji, H., Kaji, A., and Cate, J. H. (2007) Structural basis for aminoglycoside inhibition of bacterial ribosome recycling, Nat. Struct. Mol. Biol., 14, 727-732, doi: 10.1038/nsmb1271.

110. Prokhorova, I., Altman, R. B., Djumagulov, M., Shrestha, J. P., Urzhumtsev, A., Ferguson, A., Chang, C. T., Yusupov, M., Blanchard, S. C., and Yusupova, G. (2017) Aminoglyco-side interactions and impacts on the eukaryotic ribosome, Proc. Natl. Acad. Sci. USA, 114, E10899-E10908, doi: 10.1073/pnas.1715501114.

111. Krause, K. M., Serio, A. W., Kane, T. R., and Connolly, L. E. (2016) Aminoglycosides: an overview, Cold Spring Harb. Perspect. Med., 6, doi: 10.1101/cshperspect.a027029.

112. Wilhelm, J. M., Pettitt, S. E., and Jessop, J. J. (1978) Aminoglycoside antibiotics and eukaryotic protein synthesis: structure—function relationships in the stimulation of misreading with a wheat embryo system, Biochemistry, 17, 1143-1149, doi: 10.1021/bi00600a001.

113. Howard, M., Frizzell, R. A., and Bedwell, D. M. (1996) Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations, Nat. Med., 2, 467-469, doi: 10.1038/nm0496-467.

114. Kandasamy, J., Atia-Glikin, D., Shulman, E., Shapira, K., Shavit, M., Belakhov, V., and Baasov, T. (2012) Increased selectivity toward cytoplasmic versus mitochondrial ribosome confers improved efficiency of synthetic aminoglycosides in fixing damaged genes: a strategy for treatment of genetic diseases caused by nonsense mutations, J. Med. Chem., 55, 10630-10643, doi: 10.1021/jm3012992.

115. Wangen, J. R., and Green, R. (2020) Stop codon context influences genome-wide stimulation of termination codon readthrough by aminoglycosides, eLife, 9, doi: 10.7554/eLife.52611.

116. Kuang, L., Hashimoto, K., Huang, E. J., Gentry, M. S., and Zhu, H. (2020) Frontotemporal dementia non-sense mutation of progranulin rescued by aminoglycosides, Hum. Mol. Genet., 29, 624-634, doi: 10.1093/hmg/ddz280.

117. Sabbavarapu, N. M., Shavit, M., Degani, Y., Smolkin, B., Belakhov, V., and Baasov, T. (2016) Design of novel aminoglycoside derivatives with enhanced suppression of diseases-causing nonsense mutations, ACS Med. Chem. Lett., 7, 418-423, doi: 10.1021/acsmedchemlett.6b00006.

118. Shalev, M., and Baasov, T. (2014) When proteins start to make sense: fine-tuning aminoglycosides for PTC suppression therapy, Medchemcomm., 5, 1092-1105, doi: 10.1039/C4MD00081A.

119. Bidou, L., Bugaud, O., Belakhov, V., Baasov, T., and Namy, O. (2017) Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells, RNA Biol., 14, 378-388, doi: 10.1080/15476286.2017.1285480.

120. Mattis, V. B., Rai, R., Wang, J., Chang, C. W., Coady, T., and Lorson, C. L. (2006) Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts, Hum. Genet., 120, 589-601, doi: 10.1007/s00439-006-0245-7.

121. Baradaran-Heravi, A., Niesser, J., Balgi, A. D., Choi, K., Zimmerman, C., South, A. P., Anderson, H. J., Strynadka, N. C., Bally, M. B., and Roberge, M. (2017) Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity, Proc. Natl. Acad. Sci. USA, 114, 3479-3484, doi: 10.1073/pnas.1620982114.

122. Fan-Minogue, H., and Bedwell, D. M. (2008) Eukaryotic ribosomal RNA determinants of aminoglycoside resistance and their role in translational fidelity, RNA, 14, 148-157, doi: 10.1261/rna.805208.

123. Recht, M. I., Douthwaite, S., and Puglisi, J. D. (1999) Basis for prokaryotic specificity of action of aminoglycoside antibiotics, EMBO J., 18, 3133-3138, doi: 10.1093/emboj/18.11.3133.

124. Wargo, K. A., and Edwards, J. D. (2014) Aminoglycoside-induced nephrotoxicity, J. Pharm. Pract., 27, 573-577, doi: 10.1177/0897190014546836.

125. Nguyen, T., and Jeyakumar, A. (2019) Genetic susceptibility to aminoglycoside ototoxicity, Int. J. Pediatr. Otorhinolaryngol., 120, 15-19, doi: 10.1016/j.ijporl.2019.02.002.

126. Aviner, R. (2020) The science of puromycin: from studies of ribosome function to applications in biotechnology, Comput. Struct. Biotechnol. J., 18, 1074-1083, doi: 10.1016/j.csbj.2020.04.014.

127. Fritsch, C., Herrmann, A., Nothnagel, M., Szafranski, K., Huse, K., Schumann, F., Schreiber, S., Platzer, M., Krawczak, M., Hampe, J., and Brosch, M. (2012) Genome-wide search for novel human uORFs and N-terminal protein extensions using ribosomal footprinting, Genome Res., 22, 2208-2218, doi: 10.1101/gr.139568.112.

128. Hobson, B. D., Kong, L., Hartwick, E. W., Gonzalez Jr., R. L., and Sims, P. A., (2020) Elongation inhibitors do not prevent the release of puromycylated nascent polypeptide chains from ribosomes, Elife, 9, e60048, doi: 10.7554/eLife.60048.

129. Enam, S. U., Zinshteyn, B., Goldman, D. H., Cassani, M., Livingston, N. M., Seydoux, G., and Green, R. (2020) Puromycin reactivity does not accurately localize translation at the subcellular level, Elife, 9, e60303, doi: 10.7554/eLife.60303.

130. Wong, W., Bai, X. C., Sleebs, B. E., Triglia, T., Brown, A., Thompson, J. K., Jackson, K. E., Hanssen, E., Marapana, D. S., Fernandez, I. S., Ralph, S. A., Cowman, A. F., Scheres, S. H. W., and Baum, J. (2017) Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis, Nat. Microbiol., 2, 17031, doi: 10.1038/nmicrobiol.2017.31.

131. Shi, W. W., Mak, A. N., Wong, K. B., and Shaw, P. C. (2016) Structures and ribosomal interaction of ribosome-inactivating proteins, Molecules, 21, 1588, doi: 10.3390/molecules21111588.

132. Olombrada, M., Lazaro-Gorines, R., Lopez-Rodriguez, J. C., Martinez-Del-Pozo, A., Onaderra, M., Maestro-Lopez, M., Lacadena, J., Gavilanes, J. G., and Garcia-Ortega, L. (2017) Fungal ribotoxins: a review of potential biotechnological applications, Toxins, 9, 71, doi: 10.3390/toxins9020071.

133. Kozak, M., and Shatkin, A. J. (1978) Migration of 40 S ribosomal subunits on messenger RNA in the presence of edeine, J. Biol. Chem., 253, 6568-6577.

134. Vassilenko, K. S., Alekhina, O. M., Dmitriev, S. E., Shatsky, I. N., and Spirin, A. S. (2011) Unidirectional constant rate motion of the ribosomal scanning particle during eukaryotic translation initiation, Nucleic Acids Res., 39, 5555-5567, doi: 10.1093/nar/gkr147.

135. Kozak, M. (2007) Some thoughts about translational regulation: forward and backward glances, J. Cell. Biochem., 102, 280-290, doi: 10.1002/jcb.21464.

136. Contreras, A., and Carrasco, L. (1979) Selective inhibition of protein synthesis in virus-infected mammalian cells, J. Virol., 29, 114-122, doi: 10.1128/JVI.29.1.114-122.1979.

137. Baxter, R., Knell, V. C., Somerville, H. J., Swain, H. M., and Weeks, D. P. (1973) Effect of MDMP on protein synthesis in wheat and bacteria, Nat. New Biol., 243, 139-142, doi: 10.1038/newbio243139a0.

138. Mokas, S., Mills, J. R., Garreau, C., Fournier, M. J., Robert, F., Arya, P., Kaufman, R. J., Pelletier, J., and Mazroui, R. (2009) Uncoupling stress granule assembly and translation initiation inhibition, Mol. Biol. Cell, 20, 2673-2683, doi: 10.1091/mbc.E08-10-1061.

139. Weeks, D. P., and Baxter, R. (1972) Specific inhibition of peptide-chain initiation by 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamide, Biochemistry, 11, 3060-3064, doi: 10.1021/bi00766a018.

140. Baxter, R., and McGowan, J. E. (1976) MDMP action: degradative effects on polyribosomes from wheat roots and the inhibition of protein initiation, J. Exp. Bot., 27, 525-531, doi: 10.1093/jxb/27.3.525.

141. Gritz, L. R., Mitlin, J. A., Cannon, M., Littlewood, B., Carter, C. J., and Davies, J. E. (1982) Ribosome structure, maturation of ribosomal RNA and drug sensitivity in temperature-sensitive mutants of Saccharomyces cerevisiae, Mol. Gen. Genet., 188, 384-391, doi: 10.1007/BF00330038.

142. Pesce, E., Miluzio, A., Turcano, L., Minici, C., Cirino, D., Calamita, P., Manfrini, N., Oliveto, S., Ricciardi, S., Grifantini, R., Degano, M., Bresciani, A., and Biffo, S. (2020) Discovery and preliminary characterization of translational modulators that impair the binding of eIF6 to 60S ribosomal subunits, Cells, 9, doi: 10.3390/cells9010172.

143. Brina, D., Miluzio, A., Ricciardi, S., and Biffo, S. (2015) eIF6 anti-association activity is required for ribosome biogenesis, translational control and tumor progression, Biochim. Biophys. Acta, 1849, 830-835, doi: 10.1016/j.bbagrm.2014.09.010.

144. Florin, T., Maracci, C., Graf, M., Karki, P., Klepacki, D., Berninghausen, O., Beckmann, R., Vazquez-Laslop, N., Wilson, D. N., Rodnina, M. V., and Mankin, A. S. (2017) An antimicrobial peptide that inhibits translation by trapping release factors on the ribosome, Nat. Struct. Mol. Biol., 24, 752-757, doi: 10.1038/nsmb.3439.

145. Colson, G., Rabault, B., Lavelle, F., and Zerial, A. (1992) Mode of action of the antitumor compound girodazole (RP 49532A, NSC 627434), Biochem. Pharmacol., 43, 1717-1723, doi: 10.1016/0006-2952(92)90701-j.

146. Lavelle, F., Zerial, A., Fizames, C., Rabault, B., and Curaudeau, A. (1991) Antitumor activity and mechanism of action of the marine compound girodazole, Invest. New Drugs, 9, 233-244, doi: 10.1007/bf00176976.

147. Catimel, G., Coquard, R., Guastalla, J. P., Merrouche, Y., Le Bail, N., Alakl, M. K., Dumortier, A., Foy, M., and Clavel, M. (1995) Phase I study of RP 49532A, a new protein-synthesis inhibitor, in patients with advanced refractory solid tumors, Cancer chemother. Pharmacol., 35, 246-248, doi: 10.1007/BF00686555.

148. Bordeira-Carrico, R., Pego, A. P., Santos, M., and Oliveira, C. (2012) Cancer syndromes and therapy by stop-codon readthrough, Trends Mol. Med., 18, 667-678, doi: 10.1016/j.molmed.2012.09.004.

149. Mort, M., Ivanov, D., Cooper, D. N., and Chuzhanova, N. A. (2008) A meta-analysis of nonsense mutations causing human genetic disease, Hum. Mut., 29, 1037-1047, doi: 10.1002/humu.20763.

150. Keeling, K. M., Xue, X., Gunn, G., and Bedwell, D. M. (2014) Therapeutics based on stop codon readthrough, Annu. Rev. Genomics Hum. Genet., 15, 371-394, doi: 10.1146/annurev-genom-091212-153527.

151. Lee, H. L., and Dougherty, J. P. (2012) Pharmaceutical therapies to recode nonsense mutations in inherited diseases, Pharmacol. Ther., 136, 227-266, doi: 10.1016/j.pharmthera.2012.07.007.

152. Ng, M. Y., Zhang, H., Weil, A., Singh, V., Jamiolkowski, R., Baradaran-Heravi, A., Roberge, M., Jacobson, A., Friesen, W., Welch, E., Goldman, Y. E., and Cooperman, B. S. (2018) New in vitro assay measuring direct interaction of nonsense suppressors with the eukaryotic protein synthesis machinery, ACS Med. Chem. Lett., 9, 1285-1291, doi: 10.1021/acsmedchemlett.8b00472.

153. Floquet, C., Rousset, J. P., and Bidou, L. (2011) Readthrough of premature termination codons in the adenomatous polyposis coli gene restores its biological activity in human cancer cells, PloS One, 6, e24125, doi: 10.1371/journal.pone.0024125.

154. Prayle, A., and Smyth, A. R. (2010) Aminoglycoside use in cystic fibrosis: therapeutic strategies and toxicity, Curr. Opin. Pulm. Med., 16, 604-610, doi: 10.1097/MCP.0b013e32833eebfd.

155. Zingman, L. V., Park, S., Olson, T. M., Alekseev, A. E., and Terzic, A. (2007) Aminoglycoside-induced translational read-through in disease: overcoming nonsense mutations by pharmacogenetic therapy, Clin. Pharmacol. Ther., 81, 99-103, doi: 10.1038/sj.clpt.6100012.

156. Lentini, L., Melfi, R., Di Leonardo, A., Spinello, A., Barone, G., Pace, A., Palumbo Piccionello, A., and Pibiri, I. (2014) Toward a rationale for the PTC124 (Ataluren) promoted readthrough of premature stop codons: a computational approach and GFP-reporter cell-based assay, Mol. Pharm., 11, 653-664, doi: 10.1021/mp400230s.

157. Konstan, M. W., VanDevanter, D. R., Rowe, S. M., Wilschanski, M., Kerem, E., Sermet-Gaudelus, I., DiMango, E., Melotti, P., McIntosh, J., and De Boeck, K. (2020) Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF), J. Cyst. Fibros., 19, 595-601, doi: 10.1016/j.jcf.2020.01.007.

158. Zainal Abidin, N., Haq, I. J., Gardner, A. I., and Brodlie, M. (2017) Ataluren in cystic fibrosis: development, clinical studies and where are we now? Exp. Opin. Pharmacother., 18, 1363-1371, doi: 10.1080/14656566.2017.1359255.

159. Auld, D. S., Thorne, N., Maguire, W. F., and Inglese, J. (2009) Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression, Proc. Natl. Acad. Sci. USA, 106, 3585-3590, doi: 10.1073/pnas.0813345106.

160. Altamura, E., Borgatti, M., Finotti, A., Gasparello, J., Gambari, R., Spinelli, M., Castaldo, R., and Altamura, N. (2016) Chemical-induced read-through at premature termination codons determined by a rapid dual-fluorescence system based on S. cerevisiae, PloS One, 11, e0154260, doi: 10.1371/journal.pone.0154260.

161. Hamada, K., Omura, N., Taguchi, A., Baradaran-Heravi, A., Kotake, M., Arai, M., Takayama, K., Taniguchi, A., Roberge, M., and Hayashi, Y. (2019) New negamycin-based potent readthrough derivative effective against TGA-type nonsense mutations, ACS Med. Chem. Lett., 10, 1450-1456, doi: 10.1021/acsmedchemlett.9b00273.

162. Arakawa, M., Shiozuka, M., Nakayama, Y., Hara, T., Hamada, M., Kondo, S., Ikeda, D., Takahashi, Y., Sawa, R., Nonomura, Y., Sheykholeslami, K., Kondo, K., Kaga, K., Kitamura, T., Suzuki-Miyagoe, Y., Takeda, S., and Matsuda, R. (2003) Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice, J. Biochem., 134, 751-758, doi: 10.1093/jb/mvg203.

163. Olivier, N. B., Altman, R. B., Noeske, J., Basarab, G. S., Code, E., Ferguson, A. D., Gao, N., Huang, J., Juette, M. F., Livchak, S., Miller, M. D., Prince, D. B., Cate, J. H., Buurman, E. T., and Blanchard, S. C. (2014) Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome, Proc. Natl. Acad. Sci. USA, 111, 16274-16279, doi: 10.1073/pnas.1414401111.

164. Ferguson, M. W., Gerak, C. A. N., Chow, C. C. T., Rastelli, E. J., Elmore, K. E., Stahl, F., Hosseini-Farahabadi, S., Baradaran-Heravi, A., Coltart, D. M., and Roberge, M. (2019) The antimalarial drug mefloquine enhances TP53 premature termination codon readthrough by aminoglycoside G418, PloS One, 14, e0216423, doi: 10.1371/journal.pone.0216423.

165. Baradaran-Heravi, A., Balgi, A. D., Zimmerman, C., Choi, K., Shidmoossavee, F. S., Tan, J. S., Bergeaud, C., Krause, A., Flibotte, S., Shimizu, Y., Anderson, H. J., Mouly, V., Jan, E., Pfeifer, T., Jaquith, J. B., and Roberge, M. (2016) Novel small molecules potentiate premature termination codon readthrough by aminoglycosides, Nucleic Acids Res., 44, 6583-6598, doi: 10.1093/nar/gkw638.

166. Nurenberg-Goloub, E., and Tampe, R. (2019) Ribosome recycling in mRNA translation, quality control, and homeo-stasis, Biol. Chem., 401, 47-61, doi: 10.1515/hsz-2019-0279.

167. Buskirk, A. R., and Green, R. (2017) Ribosome pausing, arrest and rescue in bacteria and eukaryotes, Philos. Trans. R. Soc. Lond. B Biol. Sci., 372, 20160183, doi: 10.1098/rstb.2016.0183.

168. Hirokawa, G., Kiel, M. C., Muto, A., Selmer, M., Raj, V. S., Liljas, A., Igarashi, K., Kaji, H., and Kaji, A. (2002) Post-termination complex disassembly by ribosome recycling factor, a functional tRNA mimic, EMBO J., 21, 2272-2281, doi: 10.1093/emboj/21.9.2272.

169. Kurata, S., Shen, B., Liu, J. O., Takeuchi, N., Kaji, A., and Kaji, H. (2013) Possible steps of complete disassembly of post-termination complex by yeast eEF3 deduced from inhibition by translocation inhibitors, Nucleic Acids Res., 41, 264-276, doi: 10.1093/nar/gks958.

170. Kurata, S., Nielsen, K. H., Mitchell, S. F., Lorsch, J. R., Kaji, A., and Kaji, H. (2010) Ribosome recycling step in yeast cytoplasmic protein synthesis is catalyzed by eEF3 and ATP, Proc. Natl. Acad. Sci. USA, 107, 10854-10859, doi: 10.1073/pnas.1006247107.

171. Borg, A., Pavlov, M., and Ehrenberg, M. (2016) Mechanism of fusidic acid inhibition of RRF- and EF-G-dependent splitting of the bacterial post-termination ribosome, Nucleic Acids Res., 44, 3264-3275, doi: 10.1093/nar/gkw178.

172. Sanchez-Murcia, P. A., Cortes-Cabrera, A., and Gago, F. (2017) Structural rationale for the cross-resistance of tumor cells bearing the A399V variant of elongation factor eEF1A1 to the structurally unrelated didemnin B, ternatin, nannocystin A and ansatrienin B, J. Comput. Aided Mol. Des., 31, 915-928, doi: 10.1007/s10822-017-0066-x.

173. Carelli, J. D., Sethofer, S. G., Smith, G. A., Miller, H. R., Simard, J. L., Merrick, W. C., Jain, R. K., Ross, N. T., and Taunton, J. (2015) Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex, eLife, 4, doi: 10.7554/eLife.10222.

174. Lee, J., Currano, J. N., Carroll, P. J., and Joullie, M. M. (2012) Didemnins, tamandarins and related natural products, Nat. Prod. Rep., 29, 404-424, doi: 10.1039/c2np00065b.

175. SirDeshpande, B. V., and Toogood, P. L. (1995) Mechanism of protein synthesis inhibition by didemnin B in vitro, Biochemistry, 34, 9177-9184, doi: 10.1021/bi00028a030.

176. Shao, S., Murray, J., Brown, A., Taunton, J., Ramakrishnan, V., and Hegde, R. S. (2016) Decoding mammalian ribosome-mRNA states by translational GTPase complexes, Cell, 167, 1229-1240 e1215, doi: 10.1016/j.cell.2016.10.046.

177. Losada, A., Munoz-Alonso, M. J., Garcia, C., Sanchez-Murcia, P. A., Martinez-Leal, J. F., Dominguez, J. M., Lillo, M. P., Gago, F., and Galmarini, C. M. (2016) Translation elongation factor eEF1A2 is a novel anticancer target for the marine natural product plitidepsin, Sci. Rep., 6, 35100, doi: 10.1038/srep35100.

178. Adrio, J., Cuevas, C., Manzanares, I., and Joullie, M. M. (2007) Total synthesis and biological evaluation of tamandarin B analogues, J. Org. Chem., 72, 5129-5138, doi: 10.1021/jo070412r.

179. Lindqvist, L., Robert, F., Merrick, W., Kakeya, H., Fraser, C., Osada, H., and Pelletier, J. (2010) Inhibition of translation by cytotrienin A—a member of the ansamycin family, RNA, 16, 2404-2413, doi: 10.1261/rna.2307710.

180. Yamada, Y., Tashiro, E., Taketani, S., Imoto, M., and Kataoka, T. (2011) Mycotrienin II, a translation inhibitor that prevents ICAM-1 expression induced by pro-inflammatory cytokines, J. Antibiot. (Tokyo), 64, 361-366, doi: 10.1038/ja.2011.23.

181. Krastel, P., Roggo, S., Schirle, M., Ross, N. T., Perruccio, F., Aspesi, P., Jr., Aust, T., Buntin, K., Estoppey, D., Liechty, B., Mapa, F., Memmert, K., Miller, H., Pan, X., Riedl, R., Thibaut, C., Thomas, J., Wagner, T., Weber, E., Xie, X., Schmitt, E. K., and Hoepfner, D. (2015) Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties, Angew. Chem. Int. Ed. Engl., 54, 10149-10154, doi: 10.1002/anie.201505069.

182. Justice, M. C., Hsu, M. J., Tse, B., Ku, T., Balkovec, J., Schmatz, D., and Nielsen, J. (1998) Elongation factor 2 as a novel target for selective inhibition of fungal protein synthesis, J. Biol. Chem., 273, 3148-3151, doi: 10.1074/jbc.273.6.3148.

183. Dominguez, J. M., Kelly, V. A., Kinsman, O. S., Marriott, M. S., Gomez de las Heras, F., and Martin, J. J. (1998) Sordarins: a new class of antifungals with selective inhibition of the protein synthesis elongation cycle in yeasts, Antimicrob. Agents Chemother., 42, 2274-2278, doi: 10.1128/AAC.42.9.2274.

184. Basilio, A., Justice, M., Harris, G., Bills, G., Collado, J., de la Cruz, M., Diez, M. T., Hernandez, P., Liberator, P., Nielsen kahn, J., Pelaez, F., Platas, G., Schmatz, D., Shastry, M., Tormo, J. R., Andersen, G. R., and Vicente, F. (2006) The discovery of moriniafungin, a novel sordarin derivative produced by Morinia pestalozzioides, Bioorg. Med. Chem., 14, 560-566, doi: 10.1016/j.bmc.2005.08.046.

185. Herreros, E., Almela, M. J., Lozano, S., Gomez de las Heras, F., and Gargallo-Viola, D. (2001) Antifungal activities and cytotoxicity studies of six new azasordarins, Antimicrob. Agents Chemother., 45, 3132-3139, doi: 10.1128/AAC.45.11.3132-3139.2001.

186. Jorgensen, R., Ortiz, P. A., Carr-Schmid, A., Nissen, P., Kinzy, T. G., and Andersen, G. R. (2003) Two crystal structures demonstrate large conformational changes in the eukaryotic ribosomal translocase, Nat. Struct. Biol., 10, 379-385, doi: 10.1038/nsb923.

187. Soe, R., Mosley, R. T., Justice, M., Nielsen-Kahn, J., Shastry, M., Merrill, A. R., and Andersen, G. R. (2007) Sordarin derivatives induce a novel conformation of the yeast ribosome translocation factor eEF2, J. Biol. Chem., 282, 657-666, doi: 10.1074/jbc.M607830200.

188. Spahn, C. M., Gomez-Lorenzo, M. G., Grassucci, R. A., Jorgensen, R., Andersen, G. R., Beckmann, R., Penczek, P. A., Ballesta, J. P., and Frank, J. (2004) Domain movements of elongation factor eEF2 and the eukaryotic 80S ribosome facilitate tRNA translocation, EMBO J., 23, 1008-1019, doi: 10.1038/sj.emboj.7600102.

189. Malkin, M., and Lipmann, F. (1969) Fusidic acid: inhibition of factor T2 in reticulocyte protein synthesis, Science, 164, 71-72, doi: 10.1126/science.164.3875.71.

190. Botet, J., Rodriguez-Mateos, M., Ballesta, J. P., Revuelta, J. L., and Remacha, M. (2008) A chemical genomic screen in Saccharomyces cerevisiae reveals a role for diphthamidation of translation elongation factor 2 in inhibition of protein synthesis by sordarin, Antimicrob. Agents Chemother., 52, 1623-1629, doi: 10.1128/AAC.01603-07.

191. Yates, S. P., Jorgensen, R., Andersen, G. R., and Merrill, A. R. (2006) Stealth and mimicry by deadly bacterial toxins, Trends Biochem. Sci., 31, 123-133, doi: 10.1016/j.tibs.2005.12.007.

192. Stickel, S. A., Gomes, N. P., Frederick, B., Raben, D., and Su, T. T. (2015) Bouvardin is a radiation modulator with a novel mechanism of action, Radiat. Res., 184, 392-403, doi: 10.1667/RR14068.1.

193. Zalacain, M., Zaera, E., Vazquez, D., and Jimenez, A. (1982) The mode of action of the antitumor drug bouvardin, an inhibitor of protein synthesis in eukaryotic cells, FEBS Lett., 148, 95-97, doi: 10.1016/0014-5793(82)81250-7.

194. Rambelli, F., Brigotti, M., Zamboni, M., Denaro, M., Montanaro, L., and Sperti, S. (1989) Effect of the antibiotic purpuromycin on cell-free protein-synthesizing systems, Biochem. J., 259, 307-310, doi: 10.1042/bj2590307.

195. Baragana, B., Hallyburton, I., Lee, M. C., Norcross, N. R., Grimaldi, R., et al. (2015) A novel multiple-stage antimalarial agent that inhibits protein synthesis, Nature, 522, 315-320, doi: 10.1038/nature14451.

196. Turpaev, K. T. (2018) Translation factor eIF5A, modification with hypusine and role in regulation of gene expression. eIF5A as a target for pharmacological interventions, Biochemistry (Moscow), 83, 863-873, doi: 10.1134/S0006297918080011.

197. Dong, Z., and Zhang, J. T. (2003) EIF3 p170, a mediator of mimosine effect on protein synthesis and cell cycle progression, Mol. Biol. Cell, 14, 3942-3951, doi: 10.1091/mbc.e02-12-0784.

198. Moerke, N. J., Aktas, H., Chen, H., Cantel, S., Reibarkh, M. Y., Fahmy, A., Gross, J. D., Degterev, A., Yuan, J., Chorev, M., Halperin, J. A., and Wagner, G. (2007) Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G, Cell, 128, 257-267, doi: 10.1016/j.cell.2006.11.046.

199. Sekiyama, N., Arthanari, H., Papadopoulos, E., Rodriguez-Mias, R. A., Wagner, G., and Leger-Abraham, M. (2015) Molecular mechanism of the dual activity of 4EGI-1: dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1, Proc. Natl. Acad. Sci. USA, 112, E4036-E4045, doi: 10.1073/pnas.1512118112.

200. Papadopoulos, E., Jenni, S., Kabha, E., Takrouri, K. J., Yi, T., Salvi, N., Luna, R. E., Gavathiotis, E., Mahalingam, P., Arthanari, H., Rodriguez-Mias, R., Yefidoff-Freedman, R., Aktas, B. H., Chorev, M., Halperin, J. A., and Wagner, G. (2014) Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G, Proc. Natl. Acad. Sci. USA, 111, E3187-3195, doi: 10.1073/pnas.1410250111.

201. Shatsky, I. N., Dmitriev, S. E., Andreev, D. E., and Terenin, I. M. (2014) Transcriptome-wide studies uncover the diversity of modes of mRNA recruitment to eukaryotic ribosomes, Crit. Rev. Biochem. Mol. Biol., 49, 164-177, doi: 10.3109/10409238.2014.887051.

202. Cencic, R., Hall, D. R., Robert, F., Du, Y., Min, J., Li, L., Qui, M., Lewis, I., Kurtkaya, S., Dingledine, R., Fu, H., Kozakov, D., Vajda, S., and Pelletier, J. (2011) Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F, Proc. Natl. Acad. Sci. USA, 108, 1046-1051, doi: 10.1073/pnas.1011477108.

203. Cencic, R., Desforges, M., Hall, D. R., Kozakov, D., Du, Y., Min, J., Dingledine, R., Fu, H., Vajda, S., Talbot, P. J., and Pelletier, J. (2011) Blocking eIF4E-eIF4G interaction as a strategy to impair coronavirus replication, J. Virol., 85, 6381-6389, doi: 10.1128/JVI.00078-11.

204. Cao, J., He, L., Lin, G., Hu, C., Dong, R., Zhang, J., Zhu, H., Hu, Y., Wagner, C. R., He, Q., and Yang, B. (2014) Cap-dependent translation initiation factor, eIF4E, is the target for Ouabain-mediated inhibition of HIF-1alpha, Biochem. Pharmacol., 89, 20-30, doi: 10.1016/j.bcp.2013.12.002.

205. Huang, C. T., Hsieh, C. H., Oyang, Y. J., Huang, H. C., and Juan, H. F. (2018) A large-scale gene expression intensity-based similarity metric ford repositioning, iScience, 7, 40-52, doi: 10.1016/j.isci.2018.08.017.

206. Perne, A., Muellner, M. K., Steinrueck, M., Craig-Mueller, N., Mayerhofer, J., Schwarzinger, I., Sloane, M., Uras, I. Z., Hoermann, G., Nijman, S. M., and Mayerhofer, M. (2009) Cardiac glycosides induce cell death in human cells by inhibiting general protein synthesis, PloS One, 4, e8292, doi: 10.1371/journal.pone.0008292.

207. Hossan, M. S., Chan, Z. Y., Collins, H. M., Shipton, F. N., Butler, M. S., Rahmatullah, M., Lee, J. B., Gershkovich, P., Kagan, L., Khoo, T. J., Wiart, C., and Bradshaw, T. D. (2019) Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition, Cancer Lett., 453, 57-73, doi: 10.1016/j.canlet.2019.03.034.

208. Howard, C. M., Estrada, M., Terrero, D., Tiwari, A. K., and Raman, D. (2020) Identification of cardiac glycosides as novel inhibitors of eIF4A1-mediated translation in triple-negative breast cancer cells, Cancers, 12, doi: 10.3390/cancers12082169.

209. Kentsis, A., Topisirovic, I., Culjkovic, B., Shao, L., and Borden, K. L. (2004) Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap, Proc. Natl. Acad. Sci. USA, 101, 18105-18110, doi: 10.1073/pnas.0406927102.

210. Westman, B., Beeren, L., Grudzien, E., Stepinski, J., Worch, R., Zuberek, J., Jemielity, J., Stolarski, R., Darzynkiewicz, E., Rhoads, R. E., and Preiss, T. (2005) The antiviral drug ribavirin does not mimic the 7-methylguanosine moiety of the mRNA cap structure in vitro, RNA, 11, 1505-1513, doi: 10.1261/rna.2132505.

211. Yan, Y., Svitkin, Y., Lee, J. M., Bisaillon, M., and Pelletier, J. (2005) Ribavirin is not a functional mimic of the 7-methyl guanosine mRNA cap, RNA, 11, 1238-1244, doi: 10.1261/rna.2930805.

212. Kentsis, A., Volpon, L., Topisirovic, I., Soll, C. E., Culjkovic, B., Shao, L., and Borden, K. L. (2005) Further evidence that ribavirin interacts with eIF4E, RNA, 11, 1762-1766, doi: 10.1261/rna.2238705.

213. Tan, K., Culjkovic, B., Amri, A., and Borden, K. L. (2008) Ribavirin targets eIF4E dependent Akt survival signaling, Biochem. Biophys. Res. Commun., 375, 341-345, doi: 10.1016/j.bbrc.2008.07.163.

214. Chu, J., and Pelletier, J. (2015) Targeting the eIF4A RNA helicase as an anti-neoplastic approach, Biochim. Biophys. Acta, 1849, 781-791, doi: 10.1016/j.bbagrm.2014.09.006.

215. Naineni, S. K., Itoua Maiga, R., Cencic, R., Putnam, A. A., Amador, L. A., Rodriguez, A. D., Jankowsky, E., and Pelletier, J. (2020) A comparative study of small molecules targeting eIF4A, RNA, 26, 541-549, doi: 10.1261/rna.072884.119.

216. Cencic, R., and Pelletier, J. (2016) Hippuristanol – a potent steroid inhibitor of eukaryotic initiation factor 4A, Translation, 4, e1137381, doi: 10.1080/21690731.2015.1137381.

217. Bordeleau, M. E., Matthews, J., Wojnar, J. M., Lindqvist, L., Novac, O., Jankowsky, E., Sonenberg, N., Northcote, P., Teesdale-Spittle, P., and Pelletier, J. (2005) Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation, Proc. Natl. Acad. Sci. USA, 102, 10460-10465, doi: 10.1073/pnas.0504249102.

218. Low, W. K., Dang, Y., Schneider-Poetsch, T., Shi, Z., Choi, N. S., Merrick, W. C., Romo, D., and Liu, J. O. (2005) Inhibition of eukaryotic translation initiation by the marine natural product pateamine A, Mol. Cell, 20, 709-722, doi: 10.1016/j.molcel.2005.10.008.

219. Iwasaki, S., Iwasaki, W., Takahashi, M., Sakamoto, A., Watanabe, C., Shichino, Y., Floor, S. N., Fujiwara, K., Mito, M., Dodo, K., Sodeoka, M., Imataka, H., Honma, T., Fukuzawa, K., Ito, T., and Ingolia, N. T. (2019) The Translation inhibitor rocaglamide targets a bimolecular cavity between eIF4A and polypurine RNA, Mol. Cell, 73, 738-748 e739, doi: 10.1016/j.molcel.2018.11.026.

220. Cencic, R., Carrier, M., Galicia-Vazquez, G., Bordeleau, M. E., Sukarieh, R., Bourdeau, A., Brem, B., Teodoro, J. G., Greger, H., Tremblay, M. L., Porco, J. A., Jr., and Pelletier, J. (2009) Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol, PloS One, 4, e5223, doi: 10.1371/journal.pone.0005223.

221. Chu, J., Zhang, W., Cencic, R., O’Connor, P. B. F., Robert, F., Devine, W. G., Selznick, A., Henkel, T., Merrick, W. C., Brown, L. E., Baranov, P. V., Porco, J. A., Jr., and Pelletier, J. (2020) Rocaglates induce gain-of-function alterations to eIF4A and eIF4F, Cell Rep., 30, 2481-2488 e2485, doi: 10.1016/j.celrep.2020.02.002.

222. Low, W. K., Li, J., Zhu, M., Kommaraju, S. S., Shah-Mittal, J., Hull, K., Liu, J. O., and Romo, D. (2014) Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents, Bioorg. Med. Chem., 22, 116-125, doi: 10.1016/j.bmc.2013.11.046.

223. Tillotson, J., Kedzior, M., Guimaraes, L., Ross, A. B., Peters, T. L., Ambrose, A. J., Schmidlin, C. J., Zhang, D. D., Costa-Lotufo, L. V., Rodriguez, A. D., Schatz, J. H., and Chapman, E. (2017) ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A, Bioorg. Med. Chem. Lett., 27, 4082-4085, doi: 10.1016/j.bmcl.2017.07.045.

224. Stewart, M. L., Grollman, A. P., and Huang, M. T. (1971) Aurintricarboxylic acid: inhibitor of initiation of protein synthesis, Proc. Natl. Acad. Sci. USA, 68, 97-101, doi: 10.1073/pnas.68.1.97.

225. Huang, M. T., and Grollman, A. P. (1973) Pyrocatechol violet: an inhibitor of initiation of protein synthesis, Biochem. Biophys. Res. Commun., 53, 1049-1059, doi: 10.1016/0006-291x(73)90571-8.

226. Gonzalez, R. G., Blackburn, B. J., and Schleich, T. (1979) Fractionation and structural elucidation of the active components of aurintricarboxylic acid, a potent inhibitor of protein nucleic acid interactions, Biochim. Biophys. Acta, 562, 534-545, doi: 10.1016/0005-2787(79)90116-3.

227. Liao, L. L., Horwitz, S. B., Huang, M. T., Grollman, A. P., Steward, D., and Martin, J. (1975) Triphenylmethane dyes as inhibitors of reverse transcriptase, ribonucleic acid polymerase, and protein synthesis. Structure-activity relationships, J. Med. Chem., 18, 117-120, doi: 10.1021/jm00235a029.

228. Leader, D. P. (1972) Aurintricarboxylic acid inhibition of the binding of phenylalanyl-tRNAa to rat liver ribosomal subunits, FEBS Lett., 22, 245-248, doi: 10.1016/0014-5793(72)80055-3.

229. Contreras, A., Vazquez, D., and Carrasco, L. (1978) Inhibition, by selected antibiotics, of protein synthesis in cells growing in tissue cultures, J. Antibiot. (Tokyo), 31, 598-602, doi: 10.7164/antibiotics.31.598.

230. Novac, O., Guenier, A. S., and Pelletier, J. (2004) Inhibitors of protein synthesis identified by a high throughput multiplexed translation screen, Nucleic Acids Res., 32, 902-915, doi: 10.1093/nar/gkh235.

231. Terenin, I. M., Dmitriev, S. E., Andreev, D. E., and Shatsky, I. N. (2008) Eukaryotic translation initiation machinery can operate in a bacterial-like mode without eIF2, Nat. Struct. Mol. Biol., 15, 836-841, doi: 10.1038/nsmb.1445.

232. Robert, F., Kapp, L. D., Khan, S. N., Acker, M. G., Kolitz, S., Kazemi, S., Kaufman, R. J., Merrick, W. C., Koromilas, A. E., Lorsch, J. R., and Pelletier, J. (2006) Initiation of protein synthesis by hepatitis C virus is refractory to reduced eIF2.GTP.Met-tRNA(i)(Met) ternary complex availability, Mol. Biol. Cell, 17, 4632-4644, doi: 10.1091/mbc.e06-06-0478.

233. Carvalho, A., Chu, J., Meinguet, C., Kiss, R., Vandenbussche, G., Masereel, B., Wouters, J., Kornienko, A., Pelletier, J., and Mathieu, V. (2017) A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis, Eur. J. Pharmacol., 805, 25-35, doi: 10.1016/j.ejphar.2017.03.034.

234. Lee, J., Kang, S. U., Kang, M. K., Chun, M. W., Jo, Y. J., Kwak, J. H., and Kim, S. (1999) Methionyl adenylate analogues as inhibitors of methionyl-tRNA synthetase, Bioorg. Med. Chem. Lett., 9, 1365-1370, doi: 10.1016/s0960-894x(99)00206-1.

235. Lee, J., Kang, M. K., Chun, M. W., Jo, Y. J., Kwak, J. H., and Kim, S. (1998) Methionine analogues as inhibitors of methionyl-tRNA synthetase, Bioorg. Med. Chem. Lett., 8, 3511-3514, doi: 10.1016/s0960-894x(98)00642-8.

236. Nevinsky, G. A., Favorova, O. O., Lavrik, O. I., Petrova, T. D., Kochkina, L. L., and Savchenko, T. I. (1974) Fluorinated tryptophans as substrates and inhibitors of the ATP—(32P)PPi exchange reaction catalysed by tryptophanyl tRNA synthetase, FEBS Lett., 43, 135-138, doi: 10.1016/0014-5793(74)80985-3.

237. Zhao, Y., Meng, Q., Bai, L., and Zhou, H. (2014) In silico discovery of aminoacyl-tRNA synthetase inhibitors, Int. J. Mol. Sci., 15, 1358-1373, doi: 10.3390/ijms15011358.

238. Lux, M. C., Standke, L. C., and Tan, D. S. (2019) Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors, J. Antibiot. (Tokyo), 72, 325-349, doi: 10.1038/s41429-019-0171-2.

239. Francklyn, C. S., and Mullen, P. (2019) Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics, J. Biol. Chem., 294, 5365-5385, doi: 10.1074/jbc.REV118.002956.

240. Alix, J. H. (1982) Molecular aspects of the in vivo and in vitro effects of ethionine, an analog of methionine, Microbiol. Rev., 46, 281-295.

241. Fang, P., Yu, X., Jeong, S. J., Mirando, A., Chen, K., Chen, X., Kim, S., Francklyn, C. S., and Guo, M. (2015) Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase, Nat. Commun., 6, 6402, doi: 10.1038/ncomms7402.

242. el Khoury, A., and Atoui, A. (2010) Ochratoxin a: general overview and actual molecular status, Toxins, 2, 461-493, doi: 10.3390/toxins2040461.

243. Keller, T. L., Zocco, D., Sundrud, M. S., Hendrick, M., Edenius, M., Yum, J., Kim, Y. J., Lee, H. K., Cortese, J. F., Wirth, D. F., Dignam, J. D., Rao, A., Yeo, C. Y., Mazitschek, R., and Whitman, M. (2012) Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase, Nat. Chem. Biol., 8, 311-317, doi: 10.1038/nchembio.790.

244. Sundrud, M. S., Koralov, S. B., Feuerer, M., Calado, D. P., Kozhaya, A. E., Rhule-Smith, A., Lefebvre, R. E., Unutmaz, D., Mazitschek, R., Waldner, H., Whitman, M., Keller, T., and Rao, A. (2009) Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response, Science, 324, 1334-1338, doi: 10.1126/science.1172638.

245. Sarkar, J., Mao, W., Lincecum, T. L., Jr., Alley, M. R., and Martinis, S. A. (2011) Characterization of benzoxaborole-based antifungal resistance mutations demonstrates that editing depends on electrostatic stabilization of the leucyl-tRNA synthetase editing cap, FEBS Lett., 585, 2986-2991, doi: 10.1016/j.febslet.2011.08.010.

246. Marjanovic, J., and Kozmin, S. A. (2007) Spirofungin A: stereoselective synthesis and inhibition of isoleucyl-tRNA synthetase, Angew. Chem. Int. Ed. Engl., 46, 8854-8857, doi: 10.1002/anie.200702440.

247. Shimizu, T., Usui, T., Machida, K., Furuya, K., Osada, H., and Nakata, T. (2002) Chemical modification of reveromycin A and its biological activities, Bioorg. Med. Chem. Lett., 12, 3363-3366, doi: 10.1016/s0960-894x(02)00782-5.

248. Miyamoto, Y., Machida, K., Mizunuma, M., Emoto, Y., Sato, N., Miyahara, K., Hirata, D., Usui, T., Takahashi, H., Osada, H., and Miyakawa, T. (2002) Identification of Saccharomyces cerevisiae isoleucyl-tRNA synthetase as a target of the G1-specific inhibitor Reveromycin A, J. Biol. Chem., 277, 28810-28814, doi: 10.1074/jbc.M203827200.

249. Woo, J. T., Kawatani, M., Kato, M., Shinki, T., Yonezawa, T., Kanoh, N., Nakagawa, H., Takami, M., Lee, K. H., Stern, P. H., Nagai, K., and Osada, H. (2006) Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts, Proc. Natl. Acad. Sci. USA, 103, 4729-4734, doi: 10.1073/pnas.0505663103.

250. Kirillov, S., Vitali, L. A., Goldstein, B. P., Monti, F., Semenkov, Y., Makhno, V., Ripa, S., Pon, C. L., and Gualerzi, C. O. (1997) Purpuromycin: an antibiotic inhibiting tRNA aminoacylation, RNA, 3, 905-913.

251. Van de Vijver, P., Ostrowski, T., Sproat, B., Goebels, J., Rutgeerts, O., Van Aerschot, A., Waer, M., and Herdewijn, P. (2008) Aminoacyl-tRNA synthetase inhibitors as potent and synergistic immunosuppressants, J. Med. Chem., 51, 3020-3029, doi: 10.1021/jm8000746.

252. Kim, Y., Sundrud, M. S., Zhou, C., Edenius, M., Zocco, D., Powers, K., Zhang, M., Mazitschek, R., Rao, A., Yeo, C. Y., Noss, E. H., Brenner, M. B., Whitman, M., and Keller, T. L. (2020) Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells, Proc. Natl. Acad. Sci. USA, 117, 8900-8911, doi: 10.1073/pnas.1913788117.

253. Proud, C. G. (2019) Phosphorylation and Signal Transduction Pathways in Translational Control, Cold Spring Harb. Perspect. Biol., 11, a033050, doi: 10.1101/cshperspect.a033050.

254. Roux, P. P., and Topisirovic, I. (2012) Regulation of mRNA translation by signaling pathways, Cold Spring Harb. Perspect. Biol., 4, a012252, doi: 10.1101/cshperspect.a012252.

255. Thoreen, C. C. (2017) The molecular basis of mTORC1-regulated translation, Biochem. Soc. Trans., 45, 213-221, doi: 10.1042/BST20160072.

256. Siddiqui, N., and Sonenberg, N. (2015) Signalling to eIF4E in cancer, Biochemical Soc. Trans., 43, 763-772, doi: 10.1042/BST20150126.

257. Andreev, D. E., Dmitriev, S. E., Loughran, G., Terenin, I. M., Baranov, P. V., and Shatsky, I. N. (2018) Translation control of mRNAs encoding mammalian translation initiation factors, Gene, 651, 174-182, doi: 10.1016/j.gene.2018.02.013.

258. Cockman, E., Anderson, P., and Ivanov, P. (2020) TOP mRNPs: molecular mechanisms and principles of regulation, Biomolecules, 10, doi: 10.3390/biom10070969.

259. Hua, H., Kong, Q., Zhang, H., Wang, J., Luo, T., and Jiang, Y. (2019) Targeting mTOR for cancer therapy, J. Hematol. Oncol., 12, 71, doi: 10.1186/s13045-019-0754-1.

260. Anisimova, A. S., Meerson, M. B., Gerashchenko, M. V., Kulakovskiy, I. V., Dmitriev, S. E., and Gladyshev, V. N. (2020) Multifaceted deregulation of gene expression and protein synthesis with age, Proc. Natl. Acad. Sci. USA, 117, 15581-15590, doi: 10.1073/pnas.2001788117.

261. Anisimova, A. S., Alexandrov, A. I., Makarova, N. E., Gladyshev, V. N., and Dmitriev, S. E. (2018) Protein synthesis and quality control in aging, Aging, 10, 4269-4288, doi: 10.18632/aging.101721.

262. Schenone, S., Brullo, C., Musumeci, F., Radi, M., and Botta, M. (2011) ATP-competitive inhibitors of mTOR: an update, Curr. Med. Chem., 18, 2995-3014, doi: 10.2174/092986711796391651.

263. Brunn, G. J., Williams, J., Sabers, C., Wiederrecht, G., Lawrence, J. C., Jr., and Abraham, R. T. (1996) Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002, EMBO J., 15, 5256-5267.

264. Li, B. B., Qian, C., Gameiro, P. A., Liu, C. C., Jiang, T., Roberts, T. M., Struhl, K., and Zhao, J. J. (2018) Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins, Proc. Natl. Acad. Sci. USA, 115, E9325-E9332, doi: 10.1073/pnas.1805782115.

265. Donnelly, N., Gorman, A. M., Gupta, S., and Samali, A. (2013) The eIF2alpha kinases: their structures and functions, Cell. Mol. Life Sci., 70, 3493-3511, doi: 10.1007/s00018-012-1252-6.

266. Wek, R. C. (2018) Role of eIF2alpha kinases in translational control and adaptation to cellular stress, Cold Spring Harb. Perspect. Biol., 10, doi: 10.1101/cshperspect.a032870.

267. Akulich, K. A., Andreev, D. E., Terenin, I. M., Smirnova, V. V., Anisimova, A. S., Makeeva, D. S., Arkhipova, V. I., Stolboushkina, E. A., Garber, M. B., Prokofjeva, M. M., Spirin, P. V., Prassolov, V. S., Shatsky, I. N., and Dmitriev, S. E. (2016) Four translation initiation pathways employed by the leaderless mRNA in eukaryotes, Sci. Rep., 6, 37905, doi: 10.1038/srep37905.

268. Joshi, M., Kulkarni, A., and Pal, J. K. (2013) Small molecule modulators of eukaryotic initiation factor 2alpha kinases, the key regulators of protein synthesis, Biochimie, 95, 1980-1990, doi: 10.1016/j.biochi.2013.07.030.

269. Chen, T., Ozel, D., Qiao, Y., Harbinski, F., Chen, L., Denoyelle, S., He, X., Zvereva, N., Supko, J. G., Chorev, M., Halperin, J. A., and Aktas, B. H. (2011) Chemical genetics identify eIF2alpha kinase heme-regulated inhibitor as an anticancer target, Nat. Chem. Biol., 7, 610-616, doi: 10.1038/nchembio.613.

270. Ganz, J., Shacham, T., Kramer, M., Shenkman, M., Eiger, H., Weinberg, N., Iancovici, O., Roy, S., Simhaev, L., Da’adoosh, B., Engel, H., Perets, N., Barhum, Y., Portnoy, M., Offen, D., and Lederkremer, G. Z. (2020) A novel specific PERK activator reduces toxicity and extends survival in Huntington’s disease models, Sci. Rep., 10, 6875, doi: 10.1038/s41598-020-63899-4.

271. Stockwell, S. R., Platt, G., Barrie, S. E., Zoumpoulidou, G., Te Poele, R. H., Aherne, G. W., Wilson, S. C., Sheldrake, P., McDonald, E., Venet, M., Soudy, C., Elustondo, F., Rigoreau, L., Blagg, J., Workman, P., Garrett, M. D., and Mittnacht, S. (2012) Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling, PloS One, 7, e28568, doi: 10.1371/journal.pone.0028568.

272. Damgaard, C. K., and Lykke-Andersen, J. (2011) Translational coregulation of 5’TOP mRNAs by TIA-1 and TIAR, Genes Dev., 25, 2057-2068, doi: 10.1101/gad.17355911.

273. Costa-Mattioli, M., Gobert, D., Stern, E., Gamache, K., Colina, R., Cuello, C., Sossin, W., Kaufman, R., Pelletier, J., Rosenblum, K., Krnjevic, K., Lacaille, J. C., Nader, K., and Sonenberg, N. (2007) eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory, Cell, 129, 195-206, doi: 10.1016/j.cell.2007.01.050.

274. Boyce, M., Bryant, K. F., Jousse, C., Long, K., Harding, H. P., Scheuner, D., Kaufman, R. J., Ma, D., Coen, D. M., Ron, D., and Yuan, J. (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress, Science, 307, 935-939, doi: 10.1126/science.1101902.

275. Kim, S. M., Yoon, S. Y., Choi, J. E., Park, J. S., Choi, J. M., Nguyen, T., and Kim, D. H. (2010) Activation of eukaryotic initiation factor-2 alpha-kinases in okadaic acid-treated neurons, Neuroscience, 169, 1831-1839, doi: 10.1016/j.neuroscience.2010.06.016.

276. Wakula, P., Beullens, M., van Eynde, A., Ceulemans, H., Stalmans, W., and Bollen, M. (2006) The translation initiation factor eIF2beta is an interactor of protein phosphatase-1, Biochem. J., 400, 377-383, doi: 10.1042/BJ20060758.

277. Kolupaeva, V. (2019) Serine-threonine protein phosphatases: Lost in translation, Biochim. Biophys. Acta, Mol. Cell Res., 1866, 83-89, doi: 10.1016/j.bbamcr.2018.08.006.

278. Sidrauski, C., Acosta-Alvear, D., Khoutorsky, A., Vedantham, P., Hearn, B. R., Li, H., Gamache, K., Gallagher, C. M., Ang, K. K., Wilson, C., Okreglak, V., Ashkenazi, A., Hann, B., Nader, K., Arkin, M. R., Renslo, A. R., Sonenberg, N., and Walter, P. (2013) Pharmacolog-ical brake-release of mRNA translation enhances cognitive memory, eLife, 2, e00498, doi: 10.7554/eLife.00498.

279. Rabouw, H. H., Langereis, M. A., Anand, A. A., Visser, L. J., de Groot, R. J., Walter, P., and van Kuppeveld, F. J. M. (2019) Small molecule ISRIB suppresses the integrated stress response within a defined window of activation, Proc. Natl. Acad. Sci. USA, 116, 2097-2102, doi: 10.1073/pnas.1815767116.

280. Chen, Z., Gopalakrishnan, S. M., Bui, M. H., Soni, N. B., Warrior, U., Johnson, E. F., Donnelly, J. B., and Glaser, K. B. (2011) 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor, J. Biol. Chem., 286, 43951-43958, doi: 10.1074/jbc.M111.301291.

281. De Gassart, A., Demaria, O., Panes, R., Zaffalon, L., Ryazanov, A. G., Gilliet, M., and Martinon, F. (2016) Pharmacological eEF2K activation promotes cell death and inhibits cancer progression, EMBO Rep., 17, 1471-1484, doi: 10.15252/embr.201642194.

282. Devkota, A. K., Tavares, C. D., Warthaka, M., Abramczyk, O., Marshall, K. D., Kaoud, T. S., Gorgulu, K., Ozpolat, B., and Dalby, K. N. (2012) Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125: evidence of a common in vitro artifact, Biochemistry, 51, 2100-2112, doi: 10.1021/bi201787p.

283. Beretta, S., Gritti, L., Verpelli, C., and Sala, C. (2020) Eukaryotic elongation factor 2 kinase a pharmacological target to regulate protein translation dysfunction in neurological diseases, Neuroscience, 445, 42-49, doi: 10.1016/j.neuroscience.2020.02.015.

284. Niederberger, E., King, T. S., Russe, O. Q., and Geisslinger, G. (2015) Activation of AMPK and its impact on exercise capacity, Sports Med., 45, 1497-1509, doi: 10.1007/s40279-015-0366-z.

285. Johanns, M., Pyr Dit Ruys, S., Houddane, A., Vertommen, D., Herinckx, G., Hue, L., Proud, C. G., and Rider, M. H. (2017) Direct and indirect activation of eukaryotic elongation factor 2 kinase by AMP-activated protein kinase, Cell. Signal., 36, 212-221, doi: 10.1016/j.cellsig.2017.05.010.

286. Sitron, C. S., and Brandman, O. (2020) Detection and degradation of stalled nascent chains via ribosome-associated quality control, Annu. Rev. Biochem., 89, 417-442, doi: 10.1146/annurev-biochem-013118-110729.

287. Iordanov, M. S., Pribnow, D., Magun, J. L., Dinh, T. H., Pearson, J. A., Chen, S. L., and Magun, B. E. (1997) Ribotoxic stress response: activation of the stress-activated protein kinase JNK1 by inhibitors of the peptidyl transferase reaction and by sequence-specific RNA damage to the alpha-sarcin/ricin loop in the 28S rRNA, Mol. Cell. Biol., 17, 3373-3381, doi: 10.1128/mcb.17.6.3373.

288. Shifrin, V. I., and Anderson, P. (1999) Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis, J. Biol. Chem., 274, 13985-13992, doi: 10.1074/jbc.274.20.13985.

289. He, K., Zhou, H. R., and Pestka, J. J. (2012) Targets and intracellular signaling mechanisms for deoxynivalenol-induced ribosomal RNA cleavage, Toxicol. Sci., 127, 382-390, doi: 10.1093/toxsci/kfs134.

290. He, K., Zhou, H. R., and Pestka, J. J. (2012) Mechanisms for ribotoxin-induced ribosomal RNA cleavage, Toxicol. Appl. Pharmacol., 265, 10-18, doi: 10.1016/j.taap.2012.09.017.

291. Yang, G. H., Jarvis, B. B., Chung, Y. J., and Pestka, J. J. (2000) Apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to ERK, p38 MAPK, and SAPK/JNK activation, Toxicol. Appl. Pharmacol., 164, 149-160, doi: 10.1006/taap.1999.8888.

292. Li, M., and Pestka, J. J. (2008) Comparative induction of 28S ribosomal RNA cleavage by ricin and the trichothecenes deoxynivalenol and T-2 toxin in the macrophage, Toxicol. Sci., 105, 67-78, doi: 10.1093/toxsci/kfn111.

293. Lee, K. H., Nishimura, S., Matsunaga, S., Fusetani, N., Ichijo, H., Horinouchi, S., and Yoshida, M. (2006) Induction of a ribotoxic stress response that stimulates stress-activated protein kinases by 13-deoxytedanolide, an antitumor marine macrolide, Biosci. Biotechnol. Biochem., 70, 161-171, doi: 10.1271/bbb.70.161.

294. Vind, A. C., Snieckute, G., Blasius, M., Tiedje, C., Krogh, N., Bekker-Jensen, D. B., Andersen, K. L., Nordgaard, C., Tollenaere, M. A. X., Lund, A. H., Olsen, J. V., Nielsen, H., and Bekker-Jensen, S. (2020) ZAKalpha recognizes stalled ribosomes through partially redundant sensor domains, Mol. Cell, 78, 700-713 e707, doi: 10.1016/j.molcel.2020.03.021.

295. Yamada, Y., Taketani, S., Osada, H., and Kataoka, T. (2011) Cytotrienin A, a translation inhibitor that induces ectodomain shedding of TNF receptor 1 via activation of ERK and p38 MAP kinase, Eur. J. Pharmacol., 667, 113-119, doi: 10.1016/j.ejphar.2011.05.072.

296. Francis, S. P., Katz, J., Fanning, K. D., Harris, K. A., Nicholas, B. D., Lacy, M., Pagana, J., Agris, P. F., and Shin, J. B. (2013) A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity, J. Neurosci., 33, 3079-3093, doi: 10.1523/JNEUROSCI.3430-12.2013.

297. Jandhyala, D. M., Ahluwalia, A., Obrig, T., and Thorpe, C. M. (2008) ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-induced proinflammatory cytokine expression, Cell. Microbiol., 10, 1468-1477, doi: 10.1111/j.1462-5822.2008.01139.x.

298. Wang, X., Mader, M. M., Toth, J. E., Yu, X., Jin, N., Campbell, R. M., Smallwood, J. K., Christe, M. E., Chatterjee, A., Goodson, T., Jr., Vlahos, C. J., Matter, W. F., and Bloem, L. J. (2005) Complete inhibition of anisomycin and UV radiation but not cytokine induced JNK and p38 activation by an aryl-substituted dihydropyrrolopyrazole quinoline and mixed lineage kinase 7 small interfering RNA, J. Biol. Chem., 280, 19298-19305, doi: 10.1074/jbc.M413059200.

299. Sauter, K. A., Magun, E. A., Iordanov, M. S., and Magun, B. E. (2010) ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells, Cancer Biol. Ther., 10, 258-266, doi: 10.4161/cbt.10.3.12367.

300. Wolfson, R. L., and Sabatini, D. M. (2017) The dawn of the age of amino acid sensors for the mTORC1 pathway, Cell Metab., 26, 301-309, doi 10.1016/j.cmet.2017.07.001.

301. Bhat, M., Robichaud, N., Hulea, L., Sonenberg, N., Pelletier, J., and Topisirovic, I. (2015) Targeting the translation machinery in cancer, Nat. rev. Drug Discov., 14, 261-278, doi: 10.1038/nrd4505.

302. Gilles, A., Frechin, L., Natchiar, K., Biondani, G., Loeffelholz, O. V., Holvec, S., Malaval, J. L., Winum, J. Y., Klaholz, B. P., and Peyron, J. F. (2020) Targeting the human 80S ribosome in cancer: from structure to function and drug design for innovative adjuvant therapeutic strategies, Cells, 9, 629, doi: 10.3390/cells9030629.

303. Osterman, I. A., Bogdanov, A. A., Dontsova, O. A., and Sergiev, P. V. (2016) Techniques for screening translation inhibitors, Antibiotics, 5, 22, doi: 10.3390/antibiotics5030022.

304. Ivanenkov, Y. A., Zhavoronkov, A., Yamidanov, R. S., Osterman, I. A., Sergiev, P. V., Aladinskiy, V. A., Aladinskaya, A. V., Terentiev, V. A., Veselov, M. S., Ayginin, A. A., Kartsev, V. G., Skvortsov, D. A., Chemeris, A. V., Baimiev, A. K., Sofronova, A. A., Malyshev, A. S., Filkov, G. I., Bezrukov, D. S., Zagribelnyy, B. A., Putin, E. O., et al. (2019) Identification of novel antibacterials using machine learning techniques, Front. Pharmacol., 10, 913, doi: 10.3389/fphar.2019.00913.

305. Blanchard, S. C., Cooperman, B. S., and Wilson, D. N. (2010) Probing translation with small-molecule inhibitors, Chem. Biol., 17, 633-645, doi: 10.1016/j.chembiol.2010.06.003.