Opportunities and challenges for the development of covalent chemical immunomodulators

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cysteine / chemical synthesis
  • Cysteine / chemistry
  • Cysteine / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Immunologic Factors / chemical synthesis
  • Immunologic Factors / chemistry
  • Immunologic Factors / pharmacology*
  • Molecular Structure
  • Peptide Hydrolases / metabolism*
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors*
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphotransferases / antagonists & inhibitors*
  • Phosphotransferases / metabolism
  • Signal Transduction / drug effects

Substances

  • Enzyme Inhibitors
  • Immunologic Factors
  • Phosphotransferases
  • Phosphoric Monoester Hydrolases
  • Peptide Hydrolases
  • Cysteine