Medical Research

University of California, San Francisco

James Fraser, Danica Galonic Fujimori
San Francisco, CA
December 2020

The ability to use a small molecule to selectively modulate a protein has incredible therapeutic and discovery consequences.  However, most proteins lack the type of pockets that can bind a small molecule, making them “undruggable” by conventional approaches.  These proteins are often understudied not because of a lack of importance, but simply because researchers lack molecules that can bind to them.  Modern approaches like CRISPR provide a sequence-specific genetic handle on these proteins, but even when compelling new targets are uncovered investigators still lack chemical agents to modulate them specifically.  A team at the University of California, San Francisco will develop a new platform to inhibit proteins: by selectively stopping them from ever being produced in the first place.  Using a combination of small molecule synthesis, CryoEM, and ribosome profiling, they will design a new class of small molecules—Specific Tunable Obstructors of Protein Synthesis (STOPS)—that stall ribosome at specific peptide sequences.  If successful, the project would deliver a platform to modulate any target in the proteome irrespective of its catalytic activity, ability to bind ligands, or mutation status.  Additionally, by targeting a core mechanism in translation, STOPS could be used across the tree of life.

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