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<p>The complement and coagulation systems protect against injury and infection, but ill-controlled activation may cause clinical complications. Despite their efficacy in defined indications, approved complement and coagulation inhibitors remain poorly effective in complex thromboinflammatory disorders. Given their ability to broadly impair host defense, parasitic inhibitors provide a promising therapeutic avenue. Gigastasin from the giant Amazon leech was identified as complement initiation inhibitor, but its structural complexity hitherto hampered large-scale production. Here, we report high-yield bacterial expression of active, stable gigastasin, including HPLC purification and lyophilization into endotoxin-free preparations. Recombinant gigastasin potently inhibited complement activation, favoring the lectin over classical pathway, with comparable activity in human, mouse, and monkey serum. Target protease profiling revealed strong selectivity for active C1s over its zymogen, weak binding to C1r, and no interaction with other complement proteases. Intriguingly, similar selectivity patterns were observed for coagulation proteases, ascribing gigastasin potent activity against factor XIa with weaker effect on factor XIIa. Functional assays confirmed that gigastasin impairs coagulation via the intrinsic but not extrinsic pathway. Our study thereby identifies gigastasin as dual complement and coagulation inhibitor, which, alongside scalable production, favorable stability, and broad species specificity, supports the translational potential of recombinant gigastasin in thromboinflammatory disorders.</p>

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Production and characterization of gigastasin, a leech-derived inhibitor of complement and coagulation pathways

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Aleksandra Blagojevic,
  • Peter Rüthemann,
  • Kevin Widmer,
  • Marco Mannes,
  • Dilara Caglar,
  • Mateja Tiric,
  • Mathew Ebin Sovichan,
  • Richard B. Pouw,
  • Said Rabbani,
  • Markus Huber-Lang,
  • Daniel Ricklin

摘要

The complement and coagulation systems protect against injury and infection, but ill-controlled activation may cause clinical complications. Despite their efficacy in defined indications, approved complement and coagulation inhibitors remain poorly effective in complex thromboinflammatory disorders. Given their ability to broadly impair host defense, parasitic inhibitors provide a promising therapeutic avenue. Gigastasin from the giant Amazon leech was identified as complement initiation inhibitor, but its structural complexity hitherto hampered large-scale production. Here, we report high-yield bacterial expression of active, stable gigastasin, including HPLC purification and lyophilization into endotoxin-free preparations. Recombinant gigastasin potently inhibited complement activation, favoring the lectin over classical pathway, with comparable activity in human, mouse, and monkey serum. Target protease profiling revealed strong selectivity for active C1s over its zymogen, weak binding to C1r, and no interaction with other complement proteases. Intriguingly, similar selectivity patterns were observed for coagulation proteases, ascribing gigastasin potent activity against factor XIa with weaker effect on factor XIIa. Functional assays confirmed that gigastasin impairs coagulation via the intrinsic but not extrinsic pathway. Our study thereby identifies gigastasin as dual complement and coagulation inhibitor, which, alongside scalable production, favorable stability, and broad species specificity, supports the translational potential of recombinant gigastasin in thromboinflammatory disorders.