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 complex formation with rationally designed synthetic molecules. Based on this hypothesis, we have developed several classes of Protein Domain Mimics (PDMs) that faithfully reproduce structural epitopes on protein surfaces. This work has created a foundation for the development of a new class of structure? based therapeutics. Our efforts so far have focused on mimicry of a natural binding partner to inhibit complex formation. A challenge with this approach is that natural protein-protein interactions are often transient and characterized by weak binding affinities. Mimicry of one partner, therefore, often also leads to weak binders, which are undesirable as inhibitors of complex pathways in the cellular context. A new approach is, therefore, required for rational design of protein based binders that does not begin with natural complexes. This NIGMS MIRA proposal describes new starting points for PDM design by utilizing secondary and tertiary structure-grafted protein displays for high affinity sequences. We are applying the new strategy to target therapeutically important protein-protein interactions for which there are no potent inhibitors, including intrinsically disordered proteins. In this Administrative Supplement, we request funding to purchase a Microscale Thermophoresis instrument to characterize protein- ligand binding interactions. The system would significantly enhance our ability to address the specific goals in the parent grant and enhance impact of several projects at NYU. Funds for the purchase of this equipment were not requested in the original submission because MST?s improved capabilities for protein-ligand complex characterization were not anticipated.
Protein-protein interactions are vital for numerous biological processes, from cellular signaling to gene regulation, and their misregulation has been associated with a variety of diseases. Selective modulation of these interactions would, therefore, facilitate the discovery of candidate therapeutic agents for a broad range of diseases. The parent project describes approaches for developing synthetic protein mimics for targeting chosen biomolecular complexes; the administrative supplement will enhance our ability to characterize complexes.
