Dataset Information

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

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 ?M 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.

SUBMITTER: Zheng Q

PROVIDER: S-EPMC6754619 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Zheng Qinheng Q Woehl Jordan L JL Kitamura Seiya S Santos-Martins Diogo D Smedley Christopher J CJ Li Gencheng G Forli Stefano S Moses John E JE Wolan Dennis W DW Sharpless K Barry KB

Proceedings of the National Academy of Sciences of the United States of America 20190904 38

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-(f ...[more]

PMID: 31484779

Similar Datasets

Project description:Human neutrophil elastase (HNE) is a serine protease that plays vital roles in inflammation, innate immune response, and tissue remodeling processes. HNE has been actively pursued as a drug target, particularly for the treatment of cardiopulmonary diseases. Although thousands of molecules have been reported to inhibit HNE, yet very few are being evaluated in early clinical trials, with sivelestat as the only approved HNE inhibitor. We report here a novel chemotype of sulfonated nonsaccharide heparin mimetics as potent and noncompetitive inhibitors of HNE. Using a chromogenic substrate hydrolysis assay, 14 sulfonated nonsaccharide heparin mimetics were tested for their inhibitory activity against HNE. Only 12 molecules inhibited HNE with IC50 values of 0.22-88.3 μM. The inhibition of HNE by these molecules was salt-dependent. Interestingly, a specific hexa-sulfonated molecule inhibited HNE with an IC50 value of 0.22 μM via noncompetitive mechanism, as demonstrated by Michaelis-Menten kinetics. The hexa-sulfonated derivative demonstrated at least 455-, 221-, 1590-, 21-, and 381-fold selectivity indices over other heparin-binding coagulation proteins including factors IIa, Xa, IXa, XIa, and FXIIIa, respectively. At the highest concentrations tested, the molecule also did not significantly inhibit other serine proteases of plasmin, trypsin, and chymotrypsin. Further supporting its selectivity, the molecule did not show heparin-like effects on clotting times of human plasma. The molecule also did not affect the proliferation of three cell lines at a concentration as high as 10 μM. Interestingly, the hexa-sulfonated molecule also inhibited cathepsin G with an IC50 value of 0.57 μM alluding to a dual anti-inflammatory action. A computational approach was exploited to identify putative binding site(s) for this novel class of HNE inhibitors. Overall, the reported hexa-sulfonated nonsaccharide heparin mimetic serves as a new platform to develop potent, selective, and noncompetitive inhibitors of HNE for therapeutic purposes.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets