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

Qinheng Zheng; Jordan L. Woehl; Seiya Kitamura; Diogo Santos-Martins; Christopher J. Smedley; Gencheng Li; Stefano Forli; John E. Moses; Dennis W. Wolan; K. Barry Sharpless

doi:10.1073/pnas.1909972116

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

Qinheng Zheng, Jordan L. Woehl, Seiya Kitamura, Diogo Santos-Martins, Christopher J. Smedley, Gencheng Li, Stefano Forli, John E. Moses, Dennis W. Wolan, K. Barry Sharpless

Research output: Contribution to journal › Article › peer-review

122 Scopus citations

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 IC₅₀ 0.24 μM 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.

Original language	English (US)
Pages (from-to)	18808-18814
Number of pages	7
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	38
DOIs	https://doi.org/10.1073/pnas.1909972116
State	Published - Sep 17 2019
Externally published	Yes

Keywords

Agnostic
Click chemistry
Covalent inhibitor
Elastase
SuFEx

ASJC Scopus subject areas

General

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10.1073/pnas.1909972116

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Zheng, Q., Woehl, J. L., Kitamura, S., Santos-Martins, D., Smedley, C. J., Li, G., Forli, S., Moses, J. E., Wolan, D. W., & Barry Sharpless, K. (2019). SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase. Proceedings of the National Academy of Sciences of the United States of America, 116(38), 18808-18814. https://doi.org/10.1073/pnas.1909972116

Zheng, Q, Woehl, JL, Kitamura, S, Santos-Martins, D, Smedley, CJ, Li, G, Forli, S, Moses, JE, Wolan, DW & Barry Sharpless, K 2019, 'SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 38, pp. 18808-18814. https://doi.org/10.1073/pnas.1909972116

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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 IC50 0.24 μM 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.",

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AU - Woehl, Jordan L.

AU - Kitamura, Seiya

AU - Santos-Martins, Diogo

AU - Smedley, Christopher J.

AU - Li, Gencheng

AU - Forli, Stefano

AU - Moses, John E.

AU - Wolan, Dennis W.

AU - Barry Sharpless, K.

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AB - 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 IC50 0.24 μM 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.

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KW - Click chemistry

KW - Covalent inhibitor

KW - Elastase

KW - SuFEx

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

Abstract

Keywords

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