RT Journal Article
SR Electronic
T1 Hydrazines as versatile chemical biology probes and drug-discovery tools for cofactor-dependent enzymes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.17.154864
DO 10.1101/2020.06.17.154864
A1 Zongtao Lin
A1 Xie Wang
A1 Katelyn A. Bustin
A1 Lin He
A1 Radu M. Suciu
A1 Nancy Schek
A1 Mina Ahmadi
A1 Kai Hu
A1 Erika J. Olson
A1 William H. Parsons
A1 Eric S. Witze
A1 Paul D. Morton
A1 Ann M. Gregus
A1 Matthew W. Buczynski
A1 Megan L. Matthews
YR 2020
UL http://biorxiv.org/content/early/2020/06/18/2020.06.17.154864.abstract
AB 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.Competing Interest StatementM.L.M. is a founder of Zenagem, LLC.