Research on new anti-thrombotic peptides has made progress

Coagulation factor XIa (FXIa) is a key protease in the intrinsic coagulation pathway. It plays a central role in pathological thrombosis and has little impact on the normal hemostasis process. It is a safe target for the development of a new generation of anticoagulant drugs.

近期，中国科学院海洋研究所研究团队在抗凝肽发现研究方面取得进展。研究团队从南海冷泉贻贝中鉴定出一种靶向抑制FXIa的十肽KDETRTPEEL，并系统解析了其抗凝活性、靶点选择性、作用机制及体内抗血栓效果。

研究团队以南海冷泉贻贝为原料，通过蛋白酶K水解制备寡肽水解物GPk，采用活性追踪分离和高分辨质谱鉴定，结合AI工具交叉验证，从超5000条肽序列的96个高置信候选结构中，遴选出20条肽进行活性验证。实验表明，8条肽显著抑制FXIa活性，命中率达40%。

Among them, the deep-sea mussel decapeptide KDETRTPEEL has the strongest inhibitory activity against FXIa, but has a weak effect on other coagulation-related enzymes of the same family, and has good overall selectivity. Experiments show that this peptide is a non-competitive inhibitor of FXIa, suggesting that its binding site may be different from traditional substrates. AF3 and molecular dynamics simulations showed that the binding of this peptide to FXIa is mainly driven by electrostatic interactions, and the charged residues on its molecule form stable salt bridges and electrostatic complementary pairs with the active pocket of FXIa. In the active site of coagulation-related enzymes such as FXIIa, the corresponding lack of electrostatic environment results in a significantly lower binding energy than FXIa, which explains the target preference of the peptide from the energy level. At the same time, combined with computational predictions and site-directed mutation experiments, several key residues for the peptide to exert its inhibitory effect on FXIa were consistently identified.

In the complex plasma environment, KDETRTPEEL preferentially prolongs APTT, with a higher potency than the previous lead peptide.PRNIFIt was improved by more than 16 times, and the in vivo anti-thrombotic effect was verified in a transgenic zebrafish model.The research provides a new paradigm for the efficient exploration of deep-sea active peptide resources and the development of anticoagulant drug leads.

Relevant research results were published in "Biological Resource Technology" (Bioresource Technology)superior. The research work was supported by the Shandong Provincial Natural Science Foundation.

论文链接

Anticoagulant activity, target selectivity and in vivo antithrombotic effect of KDETRTPEEL