Head‐to‐Tail Cyclic Peptide Inhibitors of the Interaction between Human von Willebrand Factor and Collagen

• Published in: ChemMedChem 2017-12, Vol.12 (23), p.1985-1993
• Main Authors: Guarracino, Danielle A., Oldfield, Alexis, Gentile, Kayla, Martin, Sara, Nguyen, Dylan, Barreto, Gianna, Kouba, Christopher
• Format: Article
• Language: English
• Subjects: Collagen - antagonists & inhibitors; Collagen - chemistry; Dose-Response Relationship, Drug; ELISA; Humans; Molecular Structure; peptide therapeutics; peptides; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; protease degradation; Protein Binding - drug effects; protein–protein interactions; Structure-Activity Relationship; von Willebrand Factor - antagonists & inhibitors; von Willebrand Factor - chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700522

The development of peptide‐based therapeutics is on the rise, with macrocyclic compounds providing the added stability and drug‐like characteristics sought after. Currently, therapies and preventatives for pathogenic thrombosis target platelet interactions at the site of the clot and have many complications. Herein we describe novel cyclic peptides as moderate inhibitors of the protein–protein interaction between von Willebrand factor (vWF) and collagen that initiates blood clot formation. We based our designs on two known disulfide‐containing, peptide‐based inhibitors of the vWF–collagen interaction. Replacing the disulfide with a head‐to‐tail cyclization strategy confers remarkable stability to the peptides when treated with a panel of proteases. Our peptides also showed moderate activity in our developed fluorescently linked immunosorbent assay (FLISA), similar to the most active disulfide‐containing peptide. These peptides provide a springboard for future advances in exceptionally stable, active cyclic peptides as drugs. Small but mighty: Small head‐to‐tail cyclized peptides were developed that are moderately active inhibitors of the protein–protein interaction between von Willebrand Factor and collagen that initiates thrombosis. The peptides showed exceptional stability in the cellular environment relative to similar existing cyclic peptides that use a disulfide bond.