Structure-based virtual screening and in vitro validation of inhibitors of cyclic dinucleotide phosphodiesterases ENPP1 and CdnP.
Structure-based virtual screening and in vitro validation of inhibitors of cyclic dinucleotide phosphodiesterases ENPP1 and CdnP.
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环二核苷酸磷酸二酯酶ENPP1和CdnP抑制剂基于结构的虚拟筛选和体外验证。
DOI：
10.1128/spectrum.02012-23
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发表时间：
2024-01-11
影响因子：
3.7
通讯作者：
Bishai, William R.
中科院分区：
文献类型：
--
作者：
Rohilla, Akshay;Singh, Alok Kumar;Koleske, Benjamin;Srikrishna, Geetha;Bishai, William R.
关键词：
Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are intracellular mediators of innate immune responses to cytosolic pathogen-derived and host DNA. STING agonists designed to mimic the natural host STING ligand, 2′,3′-cyclic GMP-AMP (cGAMP), are promising immunotherapeutic tools for infectious diseases and solid tumor immunotherapy. We previously characterized CdnP (Rv2837c), a specific phosphodiesterase (PDE) deployed by Mycobacterium tuberculosis (M.tb), as an enzyme that blunts host immunity by directly cleaving bacterial-derived c-di-AMP and host-derived 2′,3′-cGAMP. We hypothesized that small molecule inhibitors of bacterial and host cyclic dinucleotide PDEs, namely CdnP and the endogenous host PDE, ENPP1, might potentiate the STING pathway and act as host-directed therapies (HDTs) for tuberculosis. To this end, we employed virtual screening of an NCI compound library customized for improved oral drug properties to identify potential inhibitors of CdnP and ENPP1. Compounds identified in silico were tested for their inhibitory activity against purified CdnP and ENPP1. Using biochemical and cell-based assays, we identified compounds with low IC50 values against both PDEs. We validated increased cGAS-STING signaling in primary human macrophages exposed to 2′,3′-cGAMP in the presence of a lead ENPP1 inhibitor, E-3 (NCI-14465). Our studies provide a framework for novel HDTs that target the cGAS-STING pathway to promote M.tb containment and anti-tumor immunity. In this paper, we describe novel inhibitors of cyclic dinucleotide phosphodiesterase enzymes from Mycobacterium tuberculosis (M.tb) (CdnP) and mammals (ENPP1). The phosphodiesterase enzymes hydrolyze cyclic dinucleotides, such as 2′,3′-cyclic GMP-AMP and c-di-AMP, which are stimulator of interferon gene (STING) agonists. By blocking the hydrolysis of STING agonists, the cyclic GMP-AMP synthase (cGAS)-STING-IRF3 pathway is potentiated. There is strong evidence in tuberculosis and in cancer biology that potentiation of the cGAS-STING-IRF3 pathway leads to improved M.tb clearance and also improved antitumor responses in cancer. In addition to the identification of novel inhibitors and their biochemical characterization, we provide proof-of-concept evidence that our E-3 inhibitor potentiates the cGAS-STING-IRF3 pathway in both macrophage cell lines and also in primary human monocyte-derived macrophages.
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影响因子：
7.8
作者：
Dey B;Bishai WR
通讯作者：
Bishai WR
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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激动剂作为癌症治疗剂。
影响因子：
5.2
作者：
Amouzegar A;Chelvanambi M;Filderman JN;Storkus WJ;Luke JJ
通讯作者：
Luke JJ
影响因子：
22.7
作者：
Carozza JA;Böhnert V;Nguyen KC;Skariah G;Shaw KE;Brown JA;Rafat M;von Eyben R;Graves EE;Glenn JS;Smith M;Li L
通讯作者：
Li L