A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis
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REVIEW
A Quick Guide to SmallMolecule Inhibitors of Eukaryotic Protein Synthesis S. E. Dmitriev1,2,3,a*, D. O. Vladimirov2, and K. A. Lashkevich1 1
Belozersky Institute of PhysicoChemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia 2 Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia 3 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia a email: [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 Eukaryotic translation machinery has several specif ic features, both in the structure of its components and mechanisms of translation cycle [13]. Despite conserva tion of the functional core, eukaryotic ribosome signifi cantly differs from the bacterial one in structural details, having much in common with the archaeal ribosome. It also contains a number of eukaryotespecific elements, including additional rRNA segments, proteins, and pro tein regions [2, 3]. In the course of evolution, eukaryotes have developed uniq
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