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A Quick Guide to Small Molecule Inhibitors of Eukaryotic Protein Synthesis

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A Quick Guide to Small Molecule Inhibitors of Eukaryotic Protein Synthesis ISSN 00062979, Biochemistry (Moscow), 2020, Vol. 85, No. 11, pp. 13891421. © The Author(s) 2020. This article is an open access publication. Published in Russian in Biokhimiya, 2020, Vol. 85, No. 11, pp. 16331675. REVIEW A Quick Guide to SmallMolecule Inhibitors of Eukaryotic Protein Synthesis S. E. Dmitriev1,2,3,a*, D. O. Vladimirov2, and K. A. Lashkevich1 1Belozersky Institute of PhysicoChemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia 2Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia 3Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia aemail: [email protected] Received August 26, 2020 Revised October 4, 2020 Accepted October 4, 2020 Abstract—Eukaryotic ribosome and capdependent translation are attractive targets in the antitumor, antiviral, antiinflam matory, and antiparasitic therapies. Currently, a broad array of smallmolecule drugs is known that specifically inhibit pro tein synthesis in eukaryotic cells. Many of them are wellstudied ribosometargeting antibiotics that block translocation, the peptidyl transferase center or the polypeptide exit tunnel, modulate the binding of translation machinery components to the ribosome, and induce miscoding, premature termination or stop codon readthrough. Such inhibitors are widely used as anticancer, anthelmintic and antifungal agents in medicine, as well as fungicides in agriculture. Chemicals that affect the accuracy of stop codon recognition are promising drugs for the nonsense suppression therapy of hereditary diseases and restoration of tumor suppressor function in cancer cells. Other compounds inhibit aminoacyltRNA synthetases, transla tion factors, and components of translationassociated signaling pathways, including mTOR kinase. Some of them have antidepressant, immunosuppressive and geroprotective properties. Translation inhibitors are also used in research for gene expression analysis by ribosome profiling, as well as in cell culture techniques. In this article, we review wellstudied and less known inhibitors of eukaryotic protein synthesis (with the exception of mitochondrial and plastid translation) classified by their targets and briefly describe the action mechanisms of these compounds. We also present a continuously updated data base (http://eupsic.belozersky.msu.ru) that currently contains information on 370 inhibitors of eukaryotic protein synthesis. DOI: 10.1134/S0006297920110097 Keywords: smallmolecule drugs, 40S and 60S ribosomal subunits, 4EBP1, eIF2α phosphorylation, ribotoxic stress, cyclo heximide, harringtonine, trichothecene mycotoxins, aminoglycosides, rapamycin INTRODUCTION termination, and ribosome recycling [1, 46]. The most prominent one is the capdependent ribosomal scanning, Eukaryotic translation machinery has several specif which occurs during translation initiation and involves ic features, both in the structure of its components and loading of the 40S ribosomal subunit near the 5′end of mechanisms of translation cycle [13]. Despite conserva mRNA (that usually contains the m7Gcap) and its direc tion of the functional core, eukaryotic ribosome signifi tional movement towards the 3′end until the start cantly differs from the bacterial one in structural details, codon [1, 5]. having much in common with the archaeal ribosome. It The presence of both conserved and specific features also contains a number of eukaryotespecific elements, explains the fact that compounds suppressing protein including additional rRNA segments, proteins, and pro biosynthesis in eukaryotic cells include both universal tein regions [2, 3]. In the course of evolution, eukaryotes ribosometargeting antibiotics (active in organisms from have developed unique features of translation initiation, all kingdoms of life) and eukaryotespecific inhibitors of ribosomes or other components of the translational appa ratus. These compounds interact with different function Abbreviations: 5′TOP, 5′terminal oligopyrimidine tract; ARSase, aminoacyltRNA synthetase; DC, decoding center; al sites: the peptidyl transferase center (PTC), the Esite, GAC, GTPaseactivating center; PET, ribosomal peptide tun the polypeptide exit tunnel (PET), or the GTPaseacti nel; PTC, peptidyl transferase center. vating center (GAC) of the 60S ribosomal subunit; the * To whom correspondence should be addressed. decoding center (DC) or other sites of the 40S subunit; 1389 1390 DMITRIEV et al. the binding sites of translation factors or translation tiation, but not elongation, usually disassemble polysomes. related proteins themselves, etc. [79]. Elongation inhibitors can either disassemble or stabilize Beside acting on specific targets and having different polysomes, depending on whether they are able to act on mechanisms of action, translation inhibitors may also dif internal ribosomes in the polysome or only on the de novo fer in their effect on polysomes, which can be easily initiating ribosomes (see below). The latter statement is observed in direct experiments. Compounds that block ini not obvious and often causes confusion, so some com wortmannin LY294002 dactolisib samotosilib omipalisib methionine sulfamide ochratoxin A voxtalisib histidinol borrelidin methionyl adenylate ethionine phosmidosine febrifugine reveromycin A tavaborole torin 1, 2 halofuginone furanomycin PP242 INK128 Ku0063794 pateamine A rapamycin 4EGI1 salubrinal everolimus 4E1RCat Sal003 ridaforolimus 4E2RCat temsirolimus sordarin GM193663 bouvardin RAVII DDD107498 moriniafungin ribavirin ? purpuromycin arnamial eIFsixty4 aplidine didemnin A, B tamandarin A, B cytotrienin А mycotrienin I, II edeine MDMP nannocystin A MK28 ternatin CCT020312 silvestrol mefloquine rocaglamide A elisabatin A hippuristanol hypericin ? mefloquine ? BTdCPU PF06446846 PF0378503 tetracenomycin X G418 TC007 dabrafenib G418 paromomycin NB124 MK1775 paromomycin ataluren ? amlexanox anisomycin blasticidin S RTC14 deoxynivalenol lycorine nagilactone C BZ16 verrucarin A amicetin agelastatin A TCP1109 T2 toxin bruceantin bactobolin A hygromycin B ? narciclasine harringtonine A201A aurintricarboxylic acid paromomycin ? sparsomycin homoharringtonine puromycin pyrochatechol violet neomycin ? showdomycin girodazole cycloheximide cryptopleurine myriaporone 3/4 gallein apidaecin ? NH125 NSC119889 lactimidomycin emetine mycalamide А, B NSC119893 lissoclimide pederine hygromycin B phyllanthoside amicoumacin A pactamycin AICAR A769622 “991” Eukaryotic translation cycle, selected regulatory pathways, and the most commonly used and wellcharacterized inhibitors of protein synthe sis. The inhibitors are grouped according to the translation cycle stages, in which their targets are involved. Translation initiation: i.1, Met tRNAi binding to eIF2 and formation of the eIF2/MettRNAi/GTP ternary complex (TC); i.2, eIF4A binging to eIF4G; i.3, eIF4E binging to eIF4G; i.4, eIF4E binging to the m7Gcapped mRNA 5′end; i.5, eIF4A helicase activity during eIF4F binding to the mRNA and subse quent ribosome scanning; i.6, AUG codon recognition during scanning; i.7, eIF5B interaction with the 60S subunit; i.8, eIF6 interaction with the 60S subunit; i.9, 60S subunit recruitment to the 48S preinitiation complex (48S PIC) and formation of the 80S initiation complex (80S IC). Elongation and accompanying reactions: e.1, tRNA aminoacylation; e.2, eEF1A/GDP dissociation after delivery of aminoacyltRNA (Aa tRNA); e.3, polypeptide progression in the ribosomal tunnel; e.4, tRNA accommodation/decoding; e.5, peptidyl transferase reaction (com bined with the preceding stages of AatRNA binding and accommodation); e.6, translocation; e.7, eEF2/GDP dissociation after transloca tion. Termination: t.1, stop codon recognition; t.2, peptidyltRNA hydrolysis. Recycling: r.1, 60S subunit dissociation. Modulators of signal ing cascades: s.1s.3, activators of eIF2 kinases; s.4, eIF2 phosphatase inhibitors; s.5, PI3K inhibitors; s.6, mTOR active site inhibitors; s.7, allosteric inhibitors of mTOR in the mTORC1 complex. Inhibitors with different mechanisms of actions affecting the same stage are shown in frames. BIOCHEMISTRY (Moscow) Vol. 85 No. 11 2020 EUKARYOTIC TRANSLATION INHIBITORS 1391 pounds acting at the elongation stage (for example, har ing inhibitors act at the polypeptide elongation stage. ringtonine and lactimidomycin) are sometimes called ini These compounds include inhibitors of peptidyl trans tiation inhibitors in the literature. Termination inhibitors ferase reaction and translocation, peptide tunnel block can increase the number of ribosomes in a polysome; how ers, inducers of decoding errors (miscoding) and prema ever, compounds that cause the stop codon readthrough ture termination, as well as some other types of inhibitors usually do not modify the polysome profile. The same is with unique mechanisms of action. true for the compounds causing miscoding; they decrease Inhibitors of peptidyl transferase center. Due to its the fidelity of protein synthesis, but generally do not affect conservation, the PTC of the large ribosomal subunit is the polysomes. Premature termination inducers (e.g., the most vulnerable spot of the “proteinsynthesizing puromycin) disassembles polysomes. This issue is compli machine”. In both pro and eukaryotes, the largest num cated by the fact that some inhibitors exhibit the concen ber of inhibitors, although belonging to different chemi trationdependent effects or trigger the ribotoxic or other cal classes and interfering with the ribosome function
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