title: Discovery of a Broad-Spectrum Antiviral Compound That Inhibits Pyrimidine Biosynthesis and Establishes a Type 1 Interferon-Independent Antiviral State.
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.
authors.affiliation: 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 dhchun01@louisville.edu.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Chung
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, Kansas, USA.
authors.forename: Jennifer E
authors.identifier: 0000-0002-6813-3710
authors.initials: JE
authors.lastname: Golden
authors.affiliation: Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Adcock
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, Kansas, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Schroeder
authors.affiliation: Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Yong-Kyu
authors.initials: YK
authors.lastname: Chu
authors.affiliation: Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Julie B
authors.initials: JB
authors.lastname: Sotsky
authors.affiliation: Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Cramer
authors.affiliation: Departments of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Chilton
authors.affiliation: Division of Infectious Diseases and Northwestern HIV Translational Research Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Chisu
authors.initials: C
authors.lastname: Song
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas, USA.
authors.forename: Manu
authors.initials: M
authors.lastname: Anantpadma
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Davey
authors.affiliation: Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Aminul I
authors.initials: AI
authors.lastname: Prodhan
authors.affiliation: Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Yin
authors.affiliation: Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D011743:Pyrimidines / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D011743:Pyrimidines; C030986:pyrimidine