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Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation
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Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation
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Journal Article
Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation
2023
Overview
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.
Cyclic GMP-AMP synthase (cGAS) is critical in modulating cellular inflammation. Here, the authors report a class of cyclopeptide inhibitors of cGAS targeting protein DNA interaction and phase separation.
