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Suramin and its analogues are multi-functional inhibitors of cGAS
Xiaoman An1, Jingwen Wang1, Benzhen Duan1
1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University.
Abstract:
Upon sensing double-stranded DNA, cyclic GMP-AMP synthase (cGAS) catalyzes ATP and GTP to synthesize the cyclic dinucleotide 2',3'-cGAMP, which subsequently activates stimulator of interferon genes (STING)-mediated immune responses. Modulation of cGAS catalytic activity is crucial for treating diseases associated with the cGAS-STING pathway. Here, we found that suramin and its analogues, such as NF023, can inhibit 2',3'-cGAMP synthesis by competitively binding to cGAS. Structural analysis of the cGAS-NF023 complex reveals that NF023 binds to the active-site cleft and DNA-binding sites of cGAS, which prevents substrate access to the active site, stabilizes the activation loop in an inactive conformation and blocks cGAS-DNA binding. In addition, both suramin and NF023 disrupt cGAS-DNA phase separation, thereby potentially impairing cytosolic DNA sensing and downstream signal transduction. These findings unveil the unique mechanisms underlying cGAS inhibition by suramin and its analogues and provide the structural basis for developing cGAS inhibitors.
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