Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase

Bioorg Med Chem Lett. 2025 Jan 1:115:130007. doi: 10.1016/j.bmcl.2024.130007. Epub 2024 Nov 7.

Abstract

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is an enzyme sensor of double-stranded DNA (dsDNA) that serves to trigger activation of the cGAS-stimulator of interferon genes (STING) pathway. Excessive activation of this pathway has been demonstrated to contribute to various forms of inflammatory disease. As such, cGAS has arisen as a potential therapeutic target with broad potential applications. Using a pathway-targeted cell-based screening approach, we identified the natural product Cladophorol-A as a new class of non-cytotoxic cGAS inhibitor (cell-based IC50 = 370 nM). An X-ray co-crystal structure at 2.75 Å resolution revealed that Cladophorol-A inhibits cGAS by binding to its active site within the conserved adenosine nucleobase binding site.

Keywords: Cladophorol-A; Enzyme inhibitor; cGAS; cGAS-STING pathway inhibition.

MeSH terms

  • Adenosine Monophosphate / chemistry
  • Binding Sites
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Guanosine Monophosphate / chemistry
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nucleotidyltransferases* / antagonists & inhibitors
  • Nucleotidyltransferases* / chemistry
  • Nucleotidyltransferases* / metabolism
  • Structure-Activity Relationship

Substances

  • cGAS protein, human
  • Enzyme Inhibitors
  • Nucleotidyltransferases
  • Guanosine Monophosphate
  • Adenosine Monophosphate