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

SBIR I 期：蛋白酶激活受体 1 (PAR1) 抗炎调节剂的结构引导设计

• 批准号: 2223225
• 负责人: Christopher Dockendorff
• 金额: $ 27.47万
• 依托单位: FUNCTION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2223225&HistoricalAwards=false
• 关键词: SBIR; Phase; Structure; guided; design

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.

这个小企业创新研究 (SBIR) 第一阶段项目的更广泛影响是，将对蛋白酶激活受体 1 (PAR1) 进行更深入的结构了解，这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，这些化合物有可能提高效力和安全性。此类化合物可能代表一种用于治疗炎症相关疾病（包括肾脏疾病）的新药物类别。拟议的项目涉及确认称为 parmodulins 的小分子配体 PAR1 上的结合位点。该结合位点的详细表征将支持快速设计、合成和测试具有作为口服药物的优异特性的新型和改进的帕莫杜林。计算、结构生物学和合成方法将与 PAR1 细胞测定相结合，以确认结合位点并开发 parmodulins 更详细的结构-活性关系。预计该项目将鉴定出具有改进的安全性和稳定性的新型帕莫杜林。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优点和更广泛的影响审查标准进行评估，被认为值得支持。