Cyclotides, which are plant-derived peptides, are attractive pharmaceutical candidates with promising proteolytic stability and cell permeability.  Despite extensive efforts, generation of designer cyclotides with novel activity and specificity against pharmaceutically demanding targets of interest has proven to be challenging due to their structural complexity.

One particularly appealing target is coagulation factor Xlla (FXlla), a trypsin-like serine protease that initiates the intrinsic clotting cascade, the inhibition of which could be effective in thromboembolic and inflammatory disease.

Researchers from The University of Queensland have used an alternative approach generating a library of diversities in excess of >1012, screened against FXIIa and identified selective and potent cyclotide-based FXIIa inhibitors.  One of the analogues is not only able to inhibit the protease activity of FXIIa with a high potency (Ki=0.37 nM) and exclusivity over related proteases, but also has an improved stability profile in human serum with half-lives of more than 24 hours.

Key features:

  • Sub-nM potent and selective (3000x over plasmin and other proteases) peptide inhibitors of human β-factor XIIa
  • Discovered with an alternative approach which generates a diverse library in excess of >1012

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