2. Academic Validation
  3. An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human β-Factor XIIa in a Cyclotide Scaffold

An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human β-Factor XIIa in a Cyclotide Scaffold

  • J Am Chem Soc. 2021 Nov 10;143(44):18481-18489. doi: 10.1021/jacs.1c07574.
Wenyu Liu 1,  Simon J de Veer 2 3,  Yen-Hua Huang 2 3,  Toru Sengoku 4,  Chikako Okada 4,  Kazuhiro Ogata 4,  Christina N Zdenek 5,  Bryan G Fry 5,  Joakim E Swedberg 3,  Toby Passioura 1 2 6,  David J Craik 2 3,  Hiroaki Suga 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033, Japan.
  • 2 Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Brisbane, QLD 4072, Australia.
  • 3 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 4 Department of Biochemistry, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan.
  • 5 Venom Evolution Lab, School of Biological Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 6 School of Life and Environmental Sciences, School of Chemistry and Sydney Analytical, The University of Sydney, Sydney, NSW 2006, Australia.
PMID: 34723512 DOI: 10.1021/jacs.1c07574
Abstract

Cyclotides are plant-derived Peptides with complex structures shaped by their head-to-tail cyclic backbone and cystine knot core. These structural features underpin the native bioactivities of cyclotides, as well as their beneficial properties as pharmaceutical leads, including high proteolytic stability and cell permeability. However, their inherent structural complexity presents a challenge for cyclotide engineering, particularly for accessing libraries of sufficient chemical diversity to design potent and selective cyclotide variants. Here, we report a strategy using mRNA display enabling us to select potent cyclotide-based FXIIa inhibitors from a library comprising more than 1012 members based on the cyclotide scaffold of Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II). The most potent and selective inhibitor, cMCoFx1, has a pM inhibitory constant toward FXIIa with greater than three orders of magnitude selectivity over related serine proteases, realizing specific inhibition of the intrinsic coagulation pathway. The cocrystal structure of cMCoFx1 and FXIIa revealed interactions at several positions across the contact interface that conveyed high affinity binding, highlighting that such cyclotides are attractive cystine knot scaffolds for therapeutic development.

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