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Cell Chem Biol. 2017 Jul 20;24(7):787-800. doi: 10.1016/j.chembiol.2017.05.023. Epub 2017 Jun 22.

Privileged Electrophile Sensors: A Resource for Covalent Drug Development.

Author information

1
Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14850, USA.
2
Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14850, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: ya222@cornell.edu.

Abstract

This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing-which enables rapid reaction with an endogenous signaling electrophile-is a quintessential resource for the development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally relevant cysteines, we can simultaneously harness previously untapped moonlighting roles of enzymes linked to redox sensing.

KEYWORDS:

chemical biology methods to perturb/probe signal transduction; covalent drugs; cysteine profiling; electrophile signaling; enzyme inhibition mechanisms; privileged cysteines; redox sensing

PMID:
28648380
PMCID:
PMC5528179
DOI:
10.1016/j.chembiol.2017.05.023
[Indexed for MEDLINE]
Free PMC Article

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