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

这项小企业创新研究（SBIR） I期项目的更广泛影响是，将对蛋白酶激活受体1 （PAR1）的结构有更深入的了解，PAR1是有前途的新型抗血栓和抗炎药物的重要靶点。该项目还将支持开发针对PAR1的新化合物，这些化合物具有提高效力和安全性的潜力。这些化合物可能代表了治疗炎症相关疾病（包括肾脏疾病）的新药物类别。拟议的项目涉及确认PAR1上称为parmodulin的小分子配体的结合位点。对这一结合位点的详细描述将有助于快速设计、合成和测试新的和改进的parmodulin，这些parmodulin具有作为口服药物的优越性能。计算、结构生物学和合成方法的结合将与PAR1细胞测定相结合，以确认结合位点，并开发更详细的parmodulin的结构-活性关系。预计在该项目中将发现具有更高安全性和稳定性的新型parmodulin。该奖项反映了美国国家科学基金会的法定使命，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.