The broader impact of this Small Business Innovation Research (SBIR) Phase I project is that a deeper structural understanding will be developed of protease-activated receptor 1 (PAR1), an important target for promising new anti-thrombotic and anti-inflammatory drugs. The project will also support the development of new compounds targeting PAR1 with the potential for improved potency and safety profiles. Such compounds could represent a new drug class for the treatment of inflammation-related diseases, including kidney disease.The proposed project involves the confirmation of the binding site on PAR1 of small molecule ligands called parmodulins. A detailed characterization of this binding site will support the rapid design, synthesis, and testing of new and improved parmodulins with superior properties as oral medications. A combination of computational, structural biology, and synthetic methods will be combined with PAR1 cell assays to confirm the binding site and develop more detailed structure-activity relationships of the parmodulins. It is also anticipated that novel parmodulins will be identified in this project with improved safety and stability profiles.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
