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  2. 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

  • Microbiol Spectr. 2024 Jan 11;12(1):e0201223. doi: 10.1128/spectrum.02012-23.
Akshay Rohilla # 1 2 Alok Kumar Singh # 1 2 Benjamin Koleske 1 2 Geetha Srikrishna 1 2 William R Bishai 1 2
Affiliations

Affiliations

  • 1 Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland, USA.
  • 2 Center for Tuberculosis Research, Johns Hopkins University School of Medicine , Baltimore, Maryland, USA.
  • # Contributed equally.
Abstract

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.

Keywords

Mycobacterium tuberculosis; cyclic dinucleotide phosphodiesterase; host-directed therapy; immune evasion.

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