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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月22日

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  • Alexander M. Skeldon,
  • Li Wang,
  • Nicolas Sgarioto,
  • Ramsay E. Beveridge,
  • Silas Chan,
  • Stephane Dorich,
  • Valerie Dumais,
  • Nadine Fradet,
  • Samuel Gaudreault,
  • Philippe LeGros,
  • Daniel McKay,
  • Ria Seliniotakis,
  • Daniel V. Sietsema,
  • Lingling Zhang,
  • Marc-Olivier Boily,
  • Jason D. Burch,
  • Alex Caron,
  • Lee D. Fader,
  • Lodoe Lama,
  • Wei Xie,
  • Dinshaw J. Patel,
  • Thomas Tuschl,
  • Michael A. Crackower,
  • Kelly A. Pike

摘要

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.