American Society of Hirudotherapy

Crystal structure of thrombin in complex with S-variegin: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors

Research article published in PloS one (2011)

Last Updated: June 18, 2026Reviewed by: ASH Editorial Board
Research article — evidence reviewArticle reference
Evidence: Research reportDrug DevelopmentKoh CY et al. · PloS one, 2011

Abstract

The inhibition of thrombin is one of the important treatments of pathological blood clot formation. Variegin, isolated from the tropical bont tick, is a novel molecule exhibiting a unique 'two-modes' inhibitory property on thrombin active site (competitive before cleavage, noncompetitive after cleavage). For the better understanding of its function, we have determined the crystal structure of the human α-thrombin:synthetic-variegin complex at 2.4 Å resolution. The structure reveals a new mechanism of thrombin inhibition by disrupting the charge relay system. Based on the structure, we have designed 17 variegin variants, differing in potency, kinetics and mechanism of inhibition. The most active variant is about 70 times more potent than the FDA-approved peptidic thrombin inhibitor, hirulog-1/bivalirudin. In vivo antithrombotic effects of the variegin variants correlate well with their in vitro affinities for thrombin. Our results encourage that variegin and the variants show strong potential for the development of tunable anticoagulants.

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

Publication typeJournal ArticleResearch Support, Non-U.S. Gov't
Indexed MeSH termsAmino Acid SequenceAnimalsAntithrombinsArthropod ProteinsBinding SitesBiocatalysisCrystallography, X-RayDrug DesignHirudinsHumansKineticsModels, Molecular

Summary

The inhibition of thrombin is one of the important treatments of pathological blood clot formation.

Why This Matters for Hirudotherapy

This article describes the 2.4 Å crystal structure of human alpha-thrombin complexed with synthetic variegin, a thrombin inhibitor isolated from the tropical bont tick, and reports the design of 17 variegin variants. The abstract states the most active variant is approximately 70 times more potent than the FDA-approved peptidic thrombin inhibitor hirulog-1/bivalirudin, and that in-vivo antithrombotic effects of the variants correlate with their in-vitro affinities for thrombin. For ASH, the relevance is indirect: hirulog-1/bivalirudin is used as a benchmark comparator, though the abstract describes it only as an FDA-approved peptidic thrombin inhibitor without characterizing its relationship to hirudin. The caveat is that variegin is tick-derived, not leech-derived, and the study does not involve hirudotherapy or the leech secretome directly.

Citation

Crystal structure of thrombin in complex with S-variegin: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors

Koh CY et al. · PloS one, 2011

DOI

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