2. Academic Validation
  3. Identification of a Mycobacterium tuberculosis Cyclic Dinucleotide Phosphodiesterase Inhibitor

Identification of a Mycobacterium tuberculosis Cyclic Dinucleotide Phosphodiesterase Inhibitor

  • ACS Infect Dis. 2021 Feb 12;7(2):309-317. doi: 10.1021/acsinfecdis.0c00444.
Caroline W Karanja 1,  Kofi S Yeboah 1,  Herman O Sintim 1 2 3
Affiliations

Affiliations

  • 1 Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, United States.
  • 2 Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
  • 3 Purdue Institute of Inflammation, Immunology, and Infectious Disease, Purdue University, 610 Purdue Mall, West Lafayette, Indiana 47907, United States.
PMID: 33492938 DOI: 10.1021/acsinfecdis.0c00444
Abstract

Immune cells sense bacteria-derived c-di-GMP and c-di-AMP as well as host-derived cGAMP, which is synthesized by cGAS upon binding to the pathogen's DNA, to mount an immunological response (cytokine production) via the STING-TBK1 pathway. Successful pathogens, such as Mycobacterium tuberculosis and group B streptococcus, harbor phosphodiesterases (PDEs) that can cleave Bacterial c-di-AMP as well as host-derived cGAMP to blunt the host's response to Infection. Selective inhibitors of Bacterial cyclic dinucleotide (CDN) PDEs are needed as tool compounds to study the role(s) of CDN PDEs during Infection and they could also become bona fide antivirulence compounds, but there is a paucity of such compounds. Using a high-throughput assay, we identified six inhibitors of MTB CDN PDE (CdnP). The most potent inhibitor, C82 with an IC50 of ∼18 μM, did not inhibit the enzymatic activities of three other Bacterial CDN PDEs (Yybt, RocR, and GBS-CdnP), a viral CDN PDE (poxin) or mammalian ENPP1.

Keywords

MTB immune evasion; MTB phosphodiesterases (CdnP); antivirulence therapy; cyclic dinucleotide; innate immune system.

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