2. Academic Validation
  3. 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.
PMID: 38095464 DOI: 10.1128/spectrum.02012-23
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.

Figures
Products