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Potent Trivalent Inhibitors of Thrombin through Hybridization of Salivary Sulfopeptides from Hematophagous Arthropods
Author(s) -
Agten Stijn M.,
Watson Emma E.,
RipollRozada Jorge,
Dowman Luke J.,
Wu Mike C. L.,
Alwis Imala,
Jackson Shaun P.,
Pereira Pedro José Barbosa,
Payne Richard J.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202015127
Subject(s) - thrombin , active site , chemistry , proteases , biochemistry , coagulation , rational design , discovery and development of direct thrombin inhibitors , protease , enzyme , biology , platelet , immunology , genetics , psychiatry , psychology
Blood feeding arthropods, such as leeches, ticks, flies and mosquitoes, provide a privileged source of peptidic anticoagulant molecules. These primarily operate through inhibition of the central coagulation protease thrombin by binding to the active site and either exosite I or exosite II. Herein, we describe the rational design of a novel class of trivalent thrombin inhibitors that simultaneously block both exosites as well as the active site. These engineered hybrids were synthesized using tandem diselenide‐selenoester ligation (DSL) and native chemical ligation (NCL) reactions in one‐pot. The most potent trivalent inhibitors possessed femtomolar inhibition constants against α‐thrombin and were selective over related coagulation proteases. A lead hybrid inhibitor possessed potent anticoagulant activity, blockade of both thrombin generation and platelet aggregation in vitro and efficacy in a murine thrombosis model at 1 mg kg −1 . The rational engineering approach described here lays the foundation for the development of potent and selective inhibitors for a range of other enzymatic targets that possess multiple sites for the disruption of protein–protein interactions, in addition to an active site.