Engineering ultrapotent trivalent anticoagulants through hybridisation of salivary peptides from multiple haematophagous organisms

Haematophagous organisms are a rich source of salivary anticoagulant polypeptides that exert their activity by blocking the catalytic site and one of two positively charged exosites on the host protease thrombin. Here, we describe a molecular engineering approach to hybridise post-translationally sulfated polypeptides from different blood-feeding organisms to enhance anticoagulant activity. This led to the discovery of a triply sulfated hybrid anticoagulant, XChimera, possessing fragments from flea, leech, and fly salivary polypeptides that exhibits femtomolar inhibitory activity against thrombin. The crystallographic structure of a complex of XChimera with thrombin shows that it displays a trivalent binding mode in which it simultaneously blocks three functional sites of the protease, the active site and exosites I and II. This trivalent chimera exhibited ultrapotent anticoagulant activity in a suite of in vitro clotting assays and was also shown to possess potent in vivo antithrombotic activity in a murine model of thrombosis.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Engineering of XChimera, a triply-sulfated hybrid anticoagulant combining flea, leech, and fly salivary peptide fragments. Achieves femtomolar Ki against thrombin via trivalent binding (active site + exosites I & II). Crystal structure resolved; in vivo efficacy in murine thrombosis model.

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