Wednesday, February 5, 2025
2/5/2025
Abstract Interactions of proteins with other biomolecules regulate fundamental cellular events and misregulation of these interactions leads to disease states. Proteins often utilize small folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these folded domains we can specifically inhibit chosen protein complex formation with rationally designed synthetic molecules. Based on this hypothesis, we have developed a suite of Protein Domain Mimics (PDMs) that faithfully reproduce binding epitopes on protein surfaces. This work has created a foundation for the development of a new class of structure–based therapeutics. Equipped with our platform of PDMs, we will focus on a currently intractable class of targets in IDPs or Intrinsically Disordered Proteins. Therapeutic targeting of intrinsically disordered proteins is attractive because they interact with a multitude of partners and influence numerous signaling pathways. However, targeting of IDPs remains underexplored. We hypothesize that we can engage cellular IDPs with biomolecular receptors and scavenge them away from their natural binding partners. This strategy would constitute a distinct mechanism for targeting of IDP-mediated protein-protein interactions. In a new direction for the group, we will develop encodable ligands to sequence-specifically target double-stranded RNA, the most abundant class of cellular RNA. dsRNA has proven to be recalcitrant to therapeutic intervention; although, it is central to many biological events. In preliminary results, we have discovered a new class of molecular scaffold that can be engineered to provide sequence-specific recognition of dsRNA. Studies in each Aim will advance general approaches to inhibit protein-protein and protein-RNA complexes, and establish PDMs as distinct constructs spanning the molecular size space between small molecules and proteins.
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