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Medical ResearchUniversity of California, San FranciscoJames Fraser, Danica Galonic Fujimori
San Francisco, CA
$1,000,000
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. |