The development of anticoagulants targeting coagulation factor XIa (FXIa) is a promising strategy to reduce thrombotic risk while minimizing bleeding complications. However, FXIa inhibitory peptides derived from the deep sea remain largely unexplored. In this study, pepsin hydrolysates from the deep-sea mussel Gigantidas platifrons exhibited anticoagulant effects through prolongation of activated partial thromboplastin time (APTT) and reducing erythrocyte and platelet aggregation in a zebrafish thrombosis model. Through bioactivity-guided fractionation combined with AI-assisted virtual screening, three novel FXIa inhibitory peptides were identified: VVTRVVR (IC50 = 523 μM), TVTRLSD (IC50 = 683 μM), and VSQPRSTL (IC50 = 695 μM). These peptides selectively inhibited FXIa without affecting FXa or thrombin and prolonged APTT. Structural analyses using AlphaFold3 modeling, molecular dynamics simulations, and quantum chemical calculations revealed that binding stability was driven by electrostatic interactions with Asp189 in the S1 pocket. This work provides a strategy for discovering anticoagulant peptides.
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