Design of potent and selective cathepsin G inhibitors based on the sunflower trypsin inhibitor-1 scaffold

Swedberg, Joakim E., Li, Choi Yi, De Veer, Simon J., Wang, Conan K. and Craik, David J. (2017) Design of potent and selective cathepsin G inhibitors based on the sunflower trypsin inhibitor-1 scaffold. Journal of Medicinal Chemistry, 60 2: 658-667. doi:10.1021/acs.jmedchem.6b01509


Author Swedberg, Joakim E.
Li, Choi Yi
De Veer, Simon J.
Wang, Conan K.
Craik, David J.
Title Design of potent and selective cathepsin G inhibitors based on the sunflower trypsin inhibitor-1 scaffold
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1520-4804
0022-2623
Publication date 2017-01-26
Sub-type Article (original research)
DOI 10.1021/acs.jmedchem.6b01509
Open Access Status Not yet assessed
Volume 60
Issue 2
Start page 658
End page 667
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
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 (Ki = 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 (Ki = 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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