Discovery of a Broad-Spectrum Antiviral Compound That Inhibits Pyrimidine Biosynthesis and Establishes a Type 1 Interferon-Independent Antiviral State

  • Antimicrob Agents Chemother. 2016 Jul 22;60(8):4552-62. doi: 10.1128/AAC.00282-16.
Dong-Hoon Chung  1 ,  Jennifer E Golden  2 ,  Robert S Adcock  3 ,  Chad E Schroeder  2 ,  Yong-Kyu Chu  3 ,  Julie B Sotsky  3 ,  Daniel E Cramer  3 ,  Paula M Chilton  4 ,  Chisu Song  5 ,  Manu Anantpadma  6 ,  Robert A Davey  6 ,  Aminul I Prodhan  7 ,  Xinmin Yin  7 ,  Xiang Zhang  7
Affiliations
  • 1. Departments of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, USA [email protected].
  • 2. University of Kansas Specialized Chemistry Center, Lawrence, Kansas, USA.
  • 3. Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, USA.
  • 4. Departments of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA.
  • 5. Division of Infectious Diseases and Northwestern HIV Translational Research Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 6. Texas Biomedical Research Institute, San Antonio, Texas, USA.
  • 7. Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky, USA.
PMID: 27185801 DOI: 10.1128/AAC.00282-16
Abstract

Viral emergence and reemergence underscore the importance of developing efficacious, broad-spectrum antivirals. Here, we report the discovery of tetrahydrobenzothiazole-based compound 1, a novel, broad-spectrum Antiviral lead that was optimized from a hit compound derived from a cytopathic effect (CPE)-based Antiviral screen using Venezuelan equine encephalitis virus. Compound 1 showed Antiviral activity against a broad range of RNA viruses, including alphaviruses, flaviviruses, Influenza Virus, and ebolavirus. Mechanism-of-action studies with metabolomics and molecular approaches revealed that the compound inhibits host pyrimidine synthesis and establishes an Antiviral state by inducing a variety of interferon-stimulated genes (ISGs). Notably, the induction of the ISGs by compound 1 was independent of the production of type 1 interferons. The Antiviral activity of compound 1 was cell type dependent with a robust effect observed in human cell lines and no observed Antiviral effect in mouse cell lines. Herein, we disclose tetrahydrobenzothiazole compound 1 as a novel lead for the development of a broad-spectrum, Antiviral therapeutic and as a molecular probe to study the mechanism of the induction of ISGs that are independent of type 1 interferons.

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