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

Abstract

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.

Figure.

Eukaryotic translation cycle, selected regulatory pathways, and the most commonly used and well-characterized inhibitors of protein synthesis. The inhibitors are grouped according to the translation cycle stages, in which their targets are involved. Translation initiation: i.1, Met-tRNA_i binding to eIF2 and formation of the eIF2/Met-tRNA_i/GTP ternary complex (TC); i.2, eIF4A binging to eIF4G; i.3, eIF4E binging to eIF4G; i.4, eIF4E binging to the m⁷G-capped mRNA 5′-end; i.5, eIF4A helicase activity during eIF4F binding to the mRNA and subsequent 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 aminoacyl-tRNA (Aa-tRNA); e.3, polypeptide progression in the ribosomal tunnel; e.4, tRNA accommodation/decoding; e.5, peptidyl transferase reaction (combined with the preceding stages of Aa-tRNA binding and accommodation); e.6, translocation; e.7, eEF2/GDP dissociation after translocation. Termination: t.1, stop codon recognition; t.2, peptidyl-tRNA hydrolysis. Recycling: r.1, 60S subunit dissociation. Modulators of signaling cascades: s.1-s.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.