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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4552-4562 |
| Number of pages | 11 |
| Journal | Antimicrobial agents and chemotherapy |
| Volume | 60 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2016 |
Funding
We thank Igor Lukashevich for LCMV, Jill Steinbach for HSV-2, and Robert Tesh at the World Reference Center for Emerging Viruses and Arboviruses for VEEV TrD and WNV. We also thank BEI resources for CHIKV, JEV, YFV 17D, EV D71, and EMCV MM. Microarray experiments were performed with the assistance of the University of Louisville Genomics Facility, which is supported by the NIH, the J. G. Brown Foundation, and user fees. This work, including the efforts of Dong-Hoon Chung and Jennifer E. Golden, was funded by HHS | NIH | National Human Genome Research Institute (NHGRI) (5U54 HG005031-06). Chemistry support was provided by the NIH under grant U54HG005031 (KU SCC). Microarray experiments were performed with the assistance of the University of Louisville Genomics Facility, which is supported by NIH grant P20GM103436 (KY IDeA Networks of Biomedical Research Excellence), NIH grant P30GM106396 (University of Louisville J. G. Brown Cancer Center Phase III CoBRE), the J. G. Brown Foundation, and user fees. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
- Infectious Diseases
