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

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.