Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema

J Med Chem. 2018 Apr 12;61(7):2823-2836. doi: 10.1021/acs.jmedchem.7b01625. Epub 2018 Mar 15.


Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biological matrices was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ∼40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema.

MeSH terms

  • Animals
  • Bradykinin / metabolism
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / pharmacology*
  • Diabetes Complications / drug therapy*
  • Diabetic Retinopathy / drug therapy*
  • Edema / drug therapy
  • Eye / metabolism
  • Foot / pathology
  • Half-Life
  • Intravitreal Injections
  • Macular Edema / drug therapy*
  • Macular Edema / etiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Permeability
  • Plasma Kallikrein / antagonists & inhibitors*
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology*
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Substrate Specificity
  • Vitreous Body / chemistry
  • Vitreous Body / metabolism


  • Bridged Bicyclo Compounds
  • Protease Inhibitors
  • Plasma Kallikrein
  • Bradykinin