Skeldon Alexander M, Wang Li, Sgarioto Nicolas, Beveridge Ramsay E, Chan Silas, Dorich Stephane, Dumais Valerie, Fradet Nadine, Gaudreault Samuel, LeGros Philippe, McKay Daniel, Seliniotakis Ria, Sietsema Daniel V, Zhang Lingling, Boily Marc-Olivier, Burch Jason D, Caron Alex, Fader Lee D, Lama Lodoe, Xie Wei, Patel Dinshaw J, Tuschl Thomas, Crackower Michael A, Pike Kelly A
Ventus Therapeutics, Saint-Laurent, QC, Canada.
Ventus Therapeutics, Waltham, MA, USA.
Commun Chem. 2025 Mar 22;8(1):88. doi: 10.1038/s42004-025-01481-7.
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.
环鸟苷酸-腺苷酸合成酶（cGAS）是一种双链DNA的细胞内传感器，在结合后会引发促炎反应。在过去十年中，由于越来越多的证据表明其激活与多种外周和神经疾病有关，将cGAS作为药物发现靶点的关注度大幅提高。在这里，我们报告了先前描述的cGAS抑制剂的结合模式，同时也揭示了这种化学类型在不同物种间效力变化的结构基础。人和小鼠cGAS之间的单个苏氨酸到异亮氨酸取代驱动化合物活性，生化、细胞和体内研究均证明了这一点。最后，我们利用结构导向的设计方法，通过靶向酶活性位点内的关键相互作用，设计出一种对人和小鼠酶均具有优异效力的新型化学抑制剂。总体而言，这项工作为cGAS抑制剂的合理优化和潜在的临床前转化策略提供了框架。
