血栓类疾病严重威胁人类生命健康，但目前临床上常用的抗凝剂对患者的正常凝血功能（伤口愈合等）会产生较大损伤，增加严重出血的风险。近年来，许多研究表明凝血因子XI（fXIa）是一种具有较高安全性的血栓类疾病治疗靶标，但靶向fXIa的药物的开发尚处于起步阶段。因此，本项目将致力于开发调控fXIa活性的小型多肽类药物，进而抑制血栓的形成。本项目将基于并优化申请人之前发明的丝氨酸水解酶多肽抑制剂的开发方法，利用理性设计和定向演化等技术筛选高效、专一的fXIa多肽抑制剂，并在分子水平研究其作用机制。另外，本项目还将在动物模型上评估抑制剂的抗血栓效果及安全性。在进一步完善丝氨酸水解酶多肽抑制剂的开发方法的同时，为血栓类疾病的治疗提供更加安全、高效的抗凝剂先导药物。

Thrombotic diseases are leading causes of death and disability worldwide. Clinically used anticoagulants impair patients’ normal hemostasis and bring about high risk of severe bleeding. In this project, we aim at developing small peptides for mediating the activity of the activated coagulation factor XI (fXIa), which has been recently suggested as a safer antithrombotic target. In our previous study, we developed a strategy for designing and screening peptidic inhibitors of serine proteases. We hereby propose to optimize the development strategy and generate high-affinity and high-specificity peptidic inhibitors of fXIa through rational design and directed evolution. We will also study the inhibitory mechanism of these peptides with multiple biochemical and biophysical approaches. Meanwhile, the antithrombotic efficacy and safety of the inhibitors will be evaluated in different animal models. The purpose of this project is to further improve the strategy of peptidic inhibitor development and to provide high-potency and high-safety candidates of anticoagulants for antithrombotic therapy.