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<p>Thrombosis is built, not merely catalyzed. Across arterial and venous disease, thrombus formation depends on a succession of protein–protein interactions (PPIs) that coordinate platelet capture and activation, thromboinflammatory amplification, and assembly of membrane-bound coagulation complexes. Although active-site inhibitors and receptor antagonists have transformed antithrombotic therapy, clinical benefit is often constrained by bleeding because many targets are indispensable for everyday hemostasis when inhibited systemically. This review advances a “thrombus assembly” framework that reframes drug discovery around disrupting interfaces that organize pathologic clot growth in a context-dependent manner shaped by shear, surfaces, local cofactors, and transient complex formation. We highlight translational proof that interface blockade works in humans, focusing on VWF A1–GPIbα inhibition and GPVI-directed strategies as exemplars of lesion- and shear-dependent antiplatelet therapy. We then survey platelet adhesion and activation PPIs (VWF–GPIb, collagen–GPVI, and αIIbβ3–ligand interactions), thromboinflammatory interfaces (including P-selectin–PSGL-1 and CLEC-2–podoplanin), and opportunities to target coagulation complex assembly and thrombin exosites without directly inhibiting catalytic active sites. A modality-focused section links interface class to therapeutic format—antibodies/nanobodies, aptamers with antidotes, peptides and macrocycles, and small-molecule PPI inhibitors—and summarizes trade-offs in reversibility, half-life, manufacturability, and immunogenicity. Finally, we discuss assays that preserve interface biology (whole-blood flow systems, microfluidics, thrombin generation, and clot mechanics) and propose clinical positioning and trial endpoints for context-gated mechanisms. By targeting the contacts that assemble and stabilize thrombi, PPI disruption offers a pragmatic route toward more selective, potentially bleeding-sparing antithrombotic therapy and a roadmap for next-generation pipeline development.</p>

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Protein-protein interaction disruption as a next-generation antithrombotic strategy

  • 期刊论文

  • 发表日期：

    2026年5月18日

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  • Emadeldin M. Kamel,
  • Sally Mostafa Khadrawy,
  • Mohamed A. M. Ali,
  • Noha A. Ahmed,
  • Nour Y. S. Yassin,
  • Saleh Alkhedhairi,
  • Faris F. Aba Alkhayl,
  • Al Mokhtar Lamsabhi

摘要

Thrombosis is built, not merely catalyzed. Across arterial and venous disease, thrombus formation depends on a succession of protein–protein interactions (PPIs) that coordinate platelet capture and activation, thromboinflammatory amplification, and assembly of membrane-bound coagulation complexes. Although active-site inhibitors and receptor antagonists have transformed antithrombotic therapy, clinical benefit is often constrained by bleeding because many targets are indispensable for everyday hemostasis when inhibited systemically. This review advances a “thrombus assembly” framework that reframes drug discovery around disrupting interfaces that organize pathologic clot growth in a context-dependent manner shaped by shear, surfaces, local cofactors, and transient complex formation. We highlight translational proof that interface blockade works in humans, focusing on VWF A1–GPIbα inhibition and GPVI-directed strategies as exemplars of lesion- and shear-dependent antiplatelet therapy. We then survey platelet adhesion and activation PPIs (VWF–GPIb, collagen–GPVI, and αIIbβ3–ligand interactions), thromboinflammatory interfaces (including P-selectin–PSGL-1 and CLEC-2–podoplanin), and opportunities to target coagulation complex assembly and thrombin exosites without directly inhibiting catalytic active sites. A modality-focused section links interface class to therapeutic format—antibodies/nanobodies, aptamers with antidotes, peptides and macrocycles, and small-molecule PPI inhibitors—and summarizes trade-offs in reversibility, half-life, manufacturability, and immunogenicity. Finally, we discuss assays that preserve interface biology (whole-blood flow systems, microfluidics, thrombin generation, and clot mechanics) and propose clinical positioning and trial endpoints for context-gated mechanisms. By targeting the contacts that assemble and stabilize thrombi, PPI disruption offers a pragmatic route toward more selective, potentially bleeding-sparing antithrombotic therapy and a roadmap for next-generation pipeline development.