Structural insight into the cGAS active site explains differences between therapeutically relevant species

Cyclic GMP-AMP synthase (cGAS) is an intracellular sensor of double-stranded DNA that triggers a pro-inflammatory response upon binding. The interest in cGAS as a drug discovery target has increased substantially over the past decade due to growing evidence linking its activation to numerous peripheral and neurological diseases. Here, we report the binding mode of previously described cGAS inhibitors while also uncovering the structural basis for the interspecies potency shifts within this chemotype. A single threonine to isoleucine substitution between human and mouse cGAS drives compound activity, as demonstrated by biochemical, cellular, and in vivo studies. Finally, we utilize a structurally enabled design approach to engineer a novel chemical inhibitor with excellent potency for both human and mouse enzymes by targeting key interactions within the enzyme active site. Overall, this work provides the framework for rational optimization of cGAS inhibitors and potential preclinical translational strategies.

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Publication Details

Journal
Communications Chemistry
Published
2025-03-22
DOI
https://doi.org/10.1038/s42004-025-01481-7
Citations
10
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
8.06
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article

Structural insight into the cGAS active site explains differences between therapeutically relevant species

D.B. McKay, Nicolas Sgarioto, Stéphane Dorich, Ramsay E. Beveridge et al.
10 citations
Communications Chemistry
Ubiquitin and proteasome pathways
8.06
article

Structural insight into the cGAS active site explains differences between therapeutically relevant species

D.B. McKay, Nicolas Sgarioto, Stéphane Dorich, Ramsay E. Beveridge, Ria Seliniotakis, Michael A. Crackower, Marc-Olivier Boily, Alexander Skeldon, Thomas Tuschl, S. Y. T. Chan, Alexandre Caron, Lodoe Lama, Valérie Dumais, Jason D. Burch, Dinshaw J. Patel, Samuel Gaudreault, Wei Xie, Lee D. Fader, Li Wang, Lingling Zhang, Kelly A. Pike, Daniel V. Sietsema, Philippe LeGros, Nadine Fradet
article en
10 citations

Abstract

Cyclic GMP-AMP synthase (cGAS) is an intracellular sensor of double-stranded DNA that triggers a pro-inflammatory response upon binding. The interest in cGAS as a drug discovery target has increased substantially over the past decade due to growing evidence linking its activation to numerous peripheral and neurological diseases. Here, we report the binding mode of previously described cGAS inhibitors while also uncovering the structural basis for the interspecies potency shifts within this chemotype. A single threonine to isoleucine substitution between human and mouse cGAS drives compound activity, as demonstrated by biochemical, cellular, and in vivo studies. Finally, we utilize a structurally enabled design approach to engineer a novel chemical inhibitor with excellent potency for both human and mouse enzymes by targeting key interactions within the enzyme active site. Overall, this work provides the framework for rational optimization of cGAS inhibitors and potential preclinical translational strategies.

Communications ChemistryVol. 8(1)
Memorial Sloan Kettering Cancer Center (US), Venture Chemicals (United States) (US), Zhejiang University (CN), Rockefeller University (US)
Openalex Percentile: Top 2%
Ubiquitin and proteasome pathways
8.06
DOIOpen Access PDFOpenAlex
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