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

  • Nat Commun. 2023 Oct 2;14(1):6132. doi: 10.1038/s41467-023-41892-5.
Xiaoquan Wang  #  1 ,  Youqiao Wang  #  2 ,  Anqi Cao  1 ,  Qinhong Luo  1  3 ,  Daoyuan Chen  4 ,  Weiqi Zhao  5 ,  Jun Xu  5 ,  Qinkai Li  1  6 ,  Xianzhang Bu  7  8 ,  Junmin Quan  9  10
Affiliations
  • 1. State Key Laboratory of Chemical Oncogenomics, Guangdong Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • 2. School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou, 510006, China.
  • 3. Department of Pharmacy, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), The First Affiliated Hospital of Shenzhen University, Shenzhen, 518000, China.
  • 4. School of Bioengineering, ZhuHai Campus of Zunyi Medical University, Zhuhai, 519041, China.
  • 5. Genetics and Metabolism Department, The Children's Hospital, School of Medicine, Zhejiang University, National Clinical Research Center for Child Health, Hangzhou, 310052, China.
  • 6. Shenzhen Bay Laboratory, Shenzhen, 518055, China.
  • 7. State Key Laboratory of Chemical Oncogenomics, Guangdong Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. [email protected].
  • 8. School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou, 510006, China. [email protected].
  • 9. State Key Laboratory of Chemical Oncogenomics, Guangdong Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. [email protected].
  • 10. Shenzhen Bay Laboratory, Shenzhen, 518055, China. [email protected].
  • # Contributed equally.
PMID: 37783727 DOI: 10.1038/s41467-023-41892-5
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.

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