Poster Presentation 14th Australian Peptide Conference 2022

Potent cyclic peptide inhibitors of FXIIa discovered by mRNA display with genetic code reprogramming (#121)

Daniel J. Ford 1 2 , Nisharnthi M. Duggan 1 2 , Sarah E. Fry 1 2 , Jorge Ripoll-Rozada 3 4 , Stijn M. Agten 5 , Wenyu Liu 6 , Leo Corcilius 1 2 , Tilman M. Hackeng 5 , Rene van Oerle 5 , Henri M. H. Spronk 5 , Anneliese S. Ashhurst 1 2 7 8 , Vishnu Mini Sasi 9 10 , Joe A. Kaczmarski 9 10 , Colin J. Jackson 9 10 , Pedro José Barbosa Pereira 3 4 , Toby Passioura 1 2 6 11 12 , Hiroaki Suga 6 , Richard J. Payne 1 2
  1. School of Chemistry, The University of Sydney, Sydney, NSW, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Sydney, NSW, Australia
  3. Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
  4. Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  5. Department of Biochemistry, University of Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
  6. Department of Chemistry, Graduate School of Science, University of Tokyo, Hongo, Tokyo, Japan
  7. Charles Perkins Centre, The University of Sydney , Sydney , NSW, Australia
  8. School of Medical Sciences, Faculty of Medicine and Health , The University of Sydney, Sydney, NSW, Australia
  9. Research School of Chemistry, Australian National University, Canberra, ACT, Australia
  10. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Canberra, ACT, Australia
  11. School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
  12. Sydney Analytical, The University of Sydney, Sydney, NSW, Australia

Thrombosis is the pathology that underlies cardiovascular diseases, including venous thrombosis, heart attack and ischemic stroke.1 Collectively, these diseases are the leading cause of premature death and disability worldwide, superseding cancer.2-3Thrombosis is the abnormal formation of blood clots that restrict blood flow throughout veins and arteries, thereby starving surrounding tissues of life-sustaining oxygen and nutrients. The coagulant and inflammatory activities of contact-system plasma proteases, namely Factor XIIa (FXIIa), are implicated in thrombosis but considered dispensable for haemostasis. Inhibition of FXIIa has proven thrombo-protective in animal models and human deficiencies of the enzyme prolong activated thromboplastin time (aPTT) without inducing a bleeding phenotype.4-8 As such, FXIIa is a promising target for the development of safe anti-thrombotics. We have identified a series of potent and selective cyclic peptide inhibitors of FXIIa by application of Randomised Non-standard Peptide Integrated Discovery (RaPID), a modern form of mRNA display technology.9,10 These inhibitors were evaluated in vitro and two lead peptides demonstrated potent inhibition of intrinsic coagulation and the inflammatory cascade.

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  10. Ford, D. J.; Duggan, N. M.; Fry, S. E.; Ripoll-Rozada, J.; Agten, S. M.; Liu, W.; Corcilius, L.; Hackeng, T. M.; van Oerle, R.; Spronk, H. M. H.; Ashhurst, A. S.; Mini Sasi, V.; 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. Journal of Medicinal Chemistry 2021, 64 (11), 7853-7876.