Potent Trivalent Inhibitors of Thrombin through Hybridization of Salivary Sulfopeptides from Hematophagous Arthropods

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, w...

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Veröffentlicht in:Angewandte Chemie International Edition 2021-03, Vol.60 (10), p.5348-5356
Hauptverfasser: Agten, Stijn M., Watson, Emma E., Ripoll‐Rozada, Jorge, Dowman, Luke J., Wu, Mike C. L., Alwis, Imala, Jackson, Shaun P., Pereira, Pedro José Barbosa, Payne, Richard J.
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container_issue 10
container_start_page 5348
container_title Angewandte Chemie International Edition
container_volume 60
creator Agten, Stijn M.
Watson, Emma E.
Ripoll‐Rozada, Jorge
Dowman, Luke J.
Wu, Mike C. L.
Alwis, Imala
Jackson, Shaun P.
Pereira, Pedro José Barbosa
Payne, Richard J.
description 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. The rational design of a novel class of trivalent thrombin inhibitors is described through the hybridization of natural sulfopeptides produced by blood feeding organisms. The hybrid sulfopeptides were rapidly assembled using peptide ligation chemistry and shown to exhibit femtomolar inhibition constants against thrombin. A lead inhibitor also showed potent inhibition of thrombin generation and platelet aggregation in vitro, as well as antithrombotic effects in a murine model.
doi_str_mv 10.1002/anie.202015127
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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. The rational design of a novel class of trivalent thrombin inhibitors is described through the hybridization of natural sulfopeptides produced by blood feeding organisms. The hybrid sulfopeptides were rapidly assembled using peptide ligation chemistry and shown to exhibit femtomolar inhibition constants against thrombin. 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subjects Amblyomma - chemistry
Animals
Anopheles - chemistry
anticoagulant
Anticoagulants
Anticoagulants - chemical synthesis
Anticoagulants - metabolism
Anticoagulants - therapeutic use
Arthropods
Cascade chemical reactions
Catalytic Domain
Chemical reactions
Coagulation
Humans
Hybridization
Hybrids
Inhibitors
Leeches
Male
Mice
Mice, Inbred C57BL
Mosquitoes
peptide engineering
peptide ligation
Platelet aggregation
Platelet Aggregation Inhibitors - chemical synthesis
Platelet Aggregation Inhibitors - metabolism
Platelet Aggregation Inhibitors - therapeutic use
Protein Binding
Protein Engineering
Protein interaction
protein synthesis
Proteins
Salivary Proteins and Peptides - chemical synthesis
Salivary Proteins and Peptides - metabolism
Salivary Proteins and Peptides - therapeutic use
Thrombin
Thrombin - chemistry
Thrombin - metabolism
Thromboembolism
Thrombosis
Thrombosis - drug therapy
Ticks
Tsetse Flies - chemistry
title Potent Trivalent Inhibitors of Thrombin through Hybridization of Salivary Sulfopeptides from Hematophagous Arthropods
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