Novel platforms for the discovery of bioactive small molecules

Project Summary DNA-encoded library (DEL) technology has revolutionized the discovery of protein- binding small molecules. We have developed a novel variant of this technology in which the libraries are synthesized on tiny, hydrophilic beads using solid-phase synthesis techniques and screened by incubation with fluorescently labeled, soluble proteins. This platform will be employed to discover a plethora of new ligands for the proteasome and other proteins involved in the Ubiquitin Proteasome System (UPS). They will serve as probe molecules and drug leads for manipulating the UPS, which is critical for maintaining protein homeostasis. An additional outcome of this work will be the development of a new class of degraders that delivers a target protein directly to the proteasome without the requirement for target Ubiquitylation. Finally, a nascent system that allows screening DELs in cell-based assays will be optimized and utilized to discover proteasome activators that can be used to test models of UPS dysfunction as a root cause of aging and various degenerative diseases.