Format

Send to

Choose Destination
Bioorg Med Chem. 2019 Aug 1;27(15):3421-3439. doi: 10.1016/j.bmc.2019.05.050. Epub 2019 Jun 5.

Opportunities and challenges for the development of covalent chemical immunomodulators.

Author information

1
Departments of Biological Chemistry and Chemistry and Biochemistry, University of California Los Angeles, USA. Electronic address: kbackus@mednet.ucla.edu.
2
Departments of Biological Chemistry and Chemistry and Biochemistry, University of California Los Angeles, USA.

Abstract

Compounds that react irreversibly with cysteines have reemerged as potent and selective tools for altering protein function, serving as chemical probes and even clinically approved drugs. The exquisite sensitivity of human immune cell signaling pathways to oxidative stress indicates the likely, yet still underexploited, general utility of covalent probes for selective chemical immunomodulation. Here, we provide an overview of immunomodulatory cysteines, including identification of electrophilic compounds available to label these residues. We focus our discussion on three protein classes essential for cell signaling, which span the 'druggability' spectrum from amenable to chemical probes (kinases), somewhat druggable (proteases), to inaccessible (phosphatases). Using existing inhibitors as a guide, we identify general strategies to guide the development of covalent probes for selected undruggable classes of proteins and propose the application of such compounds to alter immune cell functions.

KEYWORDS:

Chemical immunology; Chemoproteomics; Covalent immunomodulators; Covalent inhibitors; Cysteines; Electrophiles; Kinase inhibitors; Phosphatase inhibitors; Protease inhibitors

PMID:
31204229
DOI:
10.1016/j.bmc.2019.05.050

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center