University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Molecular, Cell and Cancer Biology

Publication Date

2020-06-18

Document Type

Article Preprint

Disciplines

Amino Acids, Peptides, and Proteins | Analytical, Diagnostic and Therapeutic Techniques and Equipment | Biochemistry | Enzymes and Coenzymes

Abstract

Known chemoproteomic probes generally use warheads that tag a single type of amino acid or modified form thereof to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electron-poor enzyme cofactors, transient intermediates and chemically-labile regulatory modifications, but probes for such species are underdeveloped. Here, we have innovated a versatile class of chemoproteomic probes for this less charted hemisphere of the proteome by using hydrazine as the common chemical warhead. Its electron-rich nature allows it to react by both polar and radicaloid mechanisms and to target multiple, pharmacologically important functional classes of enzymes bearing diverse organic and inorganic cofactors. Probe attachment can be blocked by active-site-directed inhibitors, and elaboration of the warhead supports connection of a target to a lead compound. The capacity of substituted hydrazines to profile, discover and inhibit diverse cofactor-dependent enzymes enables cell and tissue imaging and makes this platform useful for enzyme and drug discovery.

Keywords

hydrazines, biochemistry, enzymes, drug discovery, chemical biology probes

Rights and Permissions

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.

DOI of Published Version

10.1101/2020.06.17.154864

Source

bioRxiv 2020.06.17.154864; doi: https://doi.org/10.1101/2020.06.17.154864. Link to preprint on bioRxiv service.

Journal/Book/Conference Title

bioRxiv

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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