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Head‐to‐Tail Cyclic Peptide Inhibitors of the Interaction between Human von Willebrand Factor and Collagen
Author(s) -
Guarracino Danielle A.,
Oldfield Alexis,
Gentile Kayla,
Martin Sara,
Nguyen Dylan,
Barreto Gianna,
Kouba Christopher
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700522
Subject(s) - cyclic peptide , peptide , von willebrand factor , chemistry , proteases , disulfide bond , biochemistry , platelet , enzyme , immunology , medicine
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.