2. Academic Validation
  3. Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase

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

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: llairson@scripps.edu.
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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