SBIR Phase I: Structure-guided design of anti-inflammatory modulators of protease-activated receptor 1 (PAR1)

这个小企业创新研究（SBIR）第一阶段项目的更广泛的影响是，将对蛋白酶激活受体1（PAR 1）进行更深入的结构理解，PAR 1是有前途的新型抗血栓和抗炎药物的重要靶点。该项目还将支持靶向PAR 1的新化合物的开发，这些化合物具有改善效力和安全性的潜力。这类化合物可能代表一种治疗炎症相关疾病的新药，包括肾脏疾病。拟议的项目包括确认小分子配体parmodulins在PAR 1上的结合位点。该结合位点的详细表征将支持作为口服药物的具有上级性质的新的和改进的parmodulins的快速设计、合成和测试。计算、结构生物学和合成方法的组合将与PAR 1细胞测定相结合，以确认结合位点并开发parmodulins的更详细的结构-活性关系。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.