SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

Zheng, Q., Woehl, J. L., Kitamura, S., Santos-Martins, D., Smedley, C. J., Li, G., Forli, S., Moses, J. E., Wolan, D. W., Sharpless, K. B. (September 2019) SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase. Proc Natl Acad Sci U S A, 116 (38). pp. 18808-18814. ISSN 0027-8424 (Print)0027-8424

URL: https://pubmed.ncbi.nlm.nih.gov/31484779/

DOI: 10.1073/pnas.1909972116

Abstract

Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC(50) 0.24 Î¼M and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification chemistry chemistry > techniques > click chemistry bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Protease bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Protease > serine protease inhibitor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > serine proteinase inhibitors chemistry > techniques
CSHL Authors:	Moses, John E.
Communities:	CSHL labs > Moses lab
Depositing User:	Matthew Dunn
Date:	17 September 2019
Date Deposited:	08 Jan 2021 17:19
Last Modified:	05 Feb 2024 21:16
PMCID:	PMC6754619
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39587

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