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.
Mildred Kissai  1 ,  Emily N Chin  1 ,  Francisco Martínez-Peña  1 ,  Ariana Sulpizio  1 ,  E Paige Stout  2 ,  Ippei Usui  2 ,  Farhana Barmare  2 ,  Brittany Sanchez  1 ,  Eduardo Esquenazi  2 ,  Robyn L Stanfield  3 ,  Ian A Wilson  3 ,  Luke L Lairson  4
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 2. Sirenas Marine Discovery, 3550 General Atomics Ct., San Diego, CA 92121, USA.
  • 3. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 4. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 39521150 DOI: 10.1016/j.bmcl.2024.130007
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.
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