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REVIEW: A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis

S. E. Dmitriev1,2,3,a*, D. O. Vladimirov2, and K. A. Lashkevich1

1Belozersky Institute of Physico-Chemical 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

* To whom correspondence should be addressed.

Received August 26, 2020; Revised October 4, 2020; Accepted October 4, 2020
Eukaryotic ribosome and cap-dependent translation are attractive targets in the antitumor, antiviral, anti-inflammatory, and antiparasitic therapies. Currently, a broad array of small-molecule drugs is known that specifically inhibit protein synthesis in eukaryotic cells. Many of them are well-studied ribosome-targeting 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 aminoacyl-tRNA synthetases, translation factors, and components of translation-associated 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 well-studied 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 database (http://eupsic.belozersky.msu.ru) that currently contains information on 370 inhibitors of eukaryotic protein synthesis.
KEY WORDS: small-molecule drugs, 40S and 60S ribosomal subunits, 4E-BP1, eIF2α phosphorylation, ribotoxic stress, cycloheximide, harringtonine, trichothecene mycotoxins, aminoglycosides, rapamycin

DOI: 10.1134/S0006297920110097