30 Therapeutic Opportunities in Translation

Abstract

The protein synthesis apparatus and signaling pathways that regulate its activity represent excellent, largely unexploited targets for small-molecule discovery. Approaches that disrupt this process can cause either qualitative or quantitative changes in mRNA expression. Interference with the function of rRNA, tRNA, or general protein factors is likely to exert effects on global protein synthesis. On the other hand, compounds that target the ribosome recruitment phase of translation have the potential to selectively inhibit gene expression. A significant portion of our current understanding of the translation process is a consequence of utilizing small molecules to chemically dissect this complex process (Pestka 1977; Vazquez 1979). Such probes have been used to perturb the translation process in vitro and in vivo, freeze short-lived intermediates that otherwise could not be studied, identify new initiation factors, and therapeutically target this process in pathogenic organisms. At a time when novel approaches for discovering new drugs to treat a range of microbial, viral, and metabolic diseases are sought, it would seem opportune to review our understanding of small molecules that target translation. Herein, we discuss various aspects of the translation process that have recently been explored as targets for small-molecule discovery. The potential for targeting this process as an anticancer approach is also addressed. Finally, we review examples of small-molecule inhibitors of translation that are clinically used as anti-infective agents.

SMALL-MOLECULE APPROACHES THAT QUALITATIVELY ALTER MRNA TRANSLATION
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