Cyclic Peptide Inhibitors of Factor XIIα for the Treatment of Thrombotic Disease — ASN Events
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  2. Poster Session 1 - Wine Tasting
  3. Cyclic Peptide Inhibitors of Factor XIIα for the Treatment of Thrombotic Disease

Cyclic Peptide Inhibitors of Factor XIIα for the Treatment of Thrombotic Disease (#237)

Dan Ford 1 2 , Nisha Duggan 1 2 , Jorge Ripoll-Rozada 3 , Pedro Pereira 3 , Toby Passioura 1 , Hiroaka Suga 4 , Richard J Payne 1 2
  1. School of Chemistry, The University of Sydney, Sydney
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Sydney
  3. IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, , Portugal
  4. School of Science, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Thrombosis and thrombo-inflammatory disorders are underlying pathologies associated with cardiovascular diseases (CVD) such as stroke and ischemic heart disease which collectively are the leading cause of death and disability globally.1 Despite the global burden of CVD, current therapeutic prevention and treatment strategies are inadequate. While the first-generation anticoagulants warfarin and heparin are still used in clinical settings, they are being phased out for many indications in favour of newly discovered direct oral anticoagulants (DOACs) that block the blood coagulation enzymes thrombin or FXa. DOACs have greater efficacy and simpler administration regimens than warfarin and heparin, but they still carry the risk of life-threatening bleeding side effects.2

 

FXII inhibitors have recently attracted significant attention as safer anticoagulants since their activity has been shown to prevent pathological thrombosis in animal models with a limited effect on haemostasis.3 Herein, we pioneer the use of Random Non-standard Peptide Integrated Discovery (RaPID) to source potent and selective macrocyclic peptide inhibitors of FXIIa.4 that demonstrate potent anticoagulation in a murine electrolytic injury model. Together, these results highlight the power of RaPID in sourcing novel modulators of enzymatic activity that when applied to FXIIa, may offer safer alternatives to anticoagulants in current use.

  1. Vaduganathan M.; Mensah, G.; Turco, J. et al. The Global Burden of Cardiovascular Diseases and Risk. J Am Coll Cardiol. 2022, 80, (25), 2361–2371.
  2. Eikelboom, J.; Merli, G. Bleeding with Direct Oral Anticoagulants vs Warfarin: Clinical Experience, Am. J. Med 2016, 129, (11), S33-S40.
  3. Stavrou, E.; Schmaier, A.H. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis. Thromb Res. 2010 125, (3), 210-215
  4. Ford, D. J.; Duggan, N. M.; Fry, S. E.; Ripoll-Rozada, J.; Agten, S. A.; Liu, W.; Corcilius, L.; Hackeng, T. M.; van Oerle, R.; Spronk, H. M. H.; Ashhurst, A. S.; Sasi, V. S.; Kaczmarski, J. A.; Jackson, C. J.; Pereira, P. J. B.; Passioura, T.; Suga, H.; Payne, R. J. Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming. J. Med. Chem. 2021 64, 7853-7876.
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