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Antimicrob Agents Chemother. 2016 May 16. pii: AAC.00282-16. [Epub ahead of print]
Discovery of a broad-spectrum antiviral compound that inhibits pyrimidine biosynthesis and establishes a type 1 interferon-independent antiviral state.
Chung DH1, Golden JE2, Adcock RS3, Schroeder CE2, Chu YK3, Sotsky JB3, Cramer DE3, Chilton PM3, Song C4, Anantpadma M5, Davey RA5, Prodhan AI6, Yin X6, Zhang X6.
Author information
Abstract
Viral emergence and re-emergence underscores the importance of the developing efficacious, broad-spectrum antivirals. Here we report the discovery of tetrahydrobenzothiazole-based compound 1: , a novel, broad-spectrum antiviral lead, which was optimized from a hit compound derived from a 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 interferons-stimulated genes (ISG). Notably, the induction of the ISGs by compound 1: was independent of the production of type 1 interferons. The antiviral activity of 1: was cell-type dependent with a robust effect observed in human cell lines and no observed antiviral effect in mouse cell lines. We herein disclose tetrahydrobenzothiazole 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 independent of type 1 interferons.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 27185801 [PubMed - as supplied by publisher]
Discovery of a broad-spectrum antiviral compound that inhibits pyrimidine biosynthesis and establishes a type 1 interferon-independent antiviral state.
Chung DH1, Golden JE2, Adcock RS3, Schroeder CE2, Chu YK3, Sotsky JB3, Cramer DE3, Chilton PM3, Song C4, Anantpadma M5, Davey RA5, Prodhan AI6, Yin X6, Zhang X6.
Author information
Abstract
Viral emergence and re-emergence underscores the importance of the developing efficacious, broad-spectrum antivirals. Here we report the discovery of tetrahydrobenzothiazole-based compound 1: , a novel, broad-spectrum antiviral lead, which was optimized from a hit compound derived from a 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 interferons-stimulated genes (ISG). Notably, the induction of the ISGs by compound 1: was independent of the production of type 1 interferons. The antiviral activity of 1: was cell-type dependent with a robust effect observed in human cell lines and no observed antiviral effect in mouse cell lines. We herein disclose tetrahydrobenzothiazole 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 independent of type 1 interferons.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 27185801 [PubMed - as supplied by publisher]