Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation

Xiaoquan Wang, Youqiao Wang, Anqi Cao, Qinhong Luo, Daoyuan Chen, Weiqi Zhao, Jun Xu, Qinkai Li, Xianzhang Bu () and Junmin Quan ()
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Xiaoquan Wang: Peking University Shenzhen Graduate School
Youqiao Wang: SunYat-sen University
Anqi Cao: Peking University Shenzhen Graduate School
Qinhong Luo: Peking University Shenzhen Graduate School
Daoyuan Chen: ZhuHai Campus of Zunyi Medical University
Weiqi Zhao: Zhejiang University, National Clinical Research Center for Child Health
Jun Xu: Zhejiang University, National Clinical Research Center for Child Health
Qinkai Li: Peking University Shenzhen Graduate School
Xianzhang Bu: Peking University Shenzhen Graduate School
Junmin Quan: Peking University Shenzhen Graduate School

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Cyclic GMP-AMP synthase (cGAS) is an essential sensor of aberrant cytosolic DNA for initiating innate immunity upon invading pathogens and cellular stress, which is considered as a potential drug target for autoimmune and autoinflammatory diseases. Here, we report the discovery of a class of cyclopeptide inhibitors of cGAS identified by an in vitro screening assay from a focused library of cyclic peptides. These cyclopeptides specifically bind to the DNA binding site of cGAS and block the binding of dsDNA with cGAS, subsequently inhibit dsDNA-induced liquid phase condensation and activation of cGAS. The specificity and potency of one optimal lead XQ2B were characterized in cellular assays. Concordantly, XQ2B inhibited herpes simplex virus-1 (HSV-1)-induced antiviral immune responses and enhanced HSV-1 infection in vitro and in vivo. Furthermore, XQ2B significantly suppressed the elevated levels of type I interferon and proinflammatory cytokines in primary macrophages from Trex1-/- mice and systemic inflammation in Trex1-/- mice. XQ2B represents the specific cGAS inhibitor targeting protein-DNA interaction and phase separation and serves as a scaffold for the development of therapies in the treatment of cGAS-dependent inflammatory diseases.

Date: 2023
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DOI: 10.1038/s41467-023-41892-5

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