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Design of Potent and Selective Cathepsin G Inhibitors Based on the Sunflower Trypsin Inhibitor‑1 Scaffold

By Joakim E. Swedberg (352655), Choi Yi Li (3662611), Simon J. de Veer (352656), Conan K. Wang (198148) and David J. Craik (13753)


Neutrophils are directly responsible for destroying invading pathogens via reactive oxygen species, antimicrobial peptides, and neutrophil serine proteases (NSPs). Imbalance between NSP activity and endogenous protease inhibitors is associated with chronic inflammatory disorders, and engineered inhibitors of NSPs are a potential therapeutic pathway. In this study we characterized the extended substrate specificity (P4–P1) of the NSP cathepsin G using a peptide substrate library. Substituting preferred cathepsin G substrate sequences into sunflower trypsin inhibitor-1 (SFTI-1) produced a potent cathepsin G inhibitor (<i>K</i><sub>i</sub> = 0.89 nM). Cathepsin G’s P2′ preference was determined by screening against a P2′ diverse SFTI-based library, and the most preferred residue at P2′ was combined in SFTI-1 with a preferred substrate sequence (P4–P2) and a nonproteinogenic P1 residue (4-guanidyl-l-phenylalanine) to produce a potent (<i>K</i><sub>i</sub> = 1.6 nM) and the most selective (≥360-fold) engineered cathepsin G inhibitor reported to date. This compound is a promising lead for further development of cathepsin G inhibitors targeting chronic inflammatory disorders

Topics: Biochemistry, Molecular Biology, Pharmacology, Biotechnology, Immunology, Infectious Diseases, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Information Systems not elsewhere classified, cathepsin G substrate sequences, cathepsin G inhibitors, reactive oxygen species, cathepsin G inhibitor, K i, peptide substrate library, SFTI, neutrophil serine proteases, NSP cathepsin G, sunflower trypsin inhibitor, Selective Cathepsin G Inhibitors
Year: 2017
DOI identifier: 10.1021/acs.jmedchem.6b01509.s003
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Provided by: FigShare
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