Blindness or vision loss associated with diabetes is expected to rise by around 30 % in the next ten years. The primary cause of this type of blindness is diabetic macular edema, due to blood vessels in the eye that leak fluid into the retina. Targeting one of the factors involved in regulating vessel permeability, plasma kallikrein (PKal), would represent a new method for treating macular edema.
Jean H. M. Feyen and a group of scientists from Bicycle Therapeutics, Cambridge, UK, and Thrombogenics, Leuven, Belgium, have screened a phage-display library to find potent and specific peptide inhibitors of PKal. By identifying bicyclic peptides that bind to the target, potency can be increased because cyclization stabilizes the formation of the epitope. The team subsequently performed substitutions at key positions of the peptides to increase the stability of the peptides in vivo.
The two most effective peptides identified were found to be highly specific for PKal, showing almost no cross-reactivity with other serine proteases. Strangely, the peptides did not significantly increase the coagulation time of blood, but this could be because PKal is not the primary trigger for coagulation to occur.
The peptides were shown to be highly stable in vitreous fluid and initial experiments in rats and mice indicated that the effects on edema were at least equivalent to previously approved drugs. While these studies remain preliminary, a new method for treating diabetic retinopathy could affect millions of people struggling with vision loss.
- Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema,
Daniel P. Teufel, Gavin Bennett, Helen Harrison, Katerine van Rietschoten, Silvia Pavan, Catherine Stace, François Le Floch, Tine Van Bergen, Elke Vermassen, Philippe Barbeaux, Tjing-Tjing Hu, Jean H. M. Feyen, Marc Vanhove,
J. Med. Chem. 2018.