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.

Identification and characterization of GLDC as host susceptibility gene to severe influenza

“…In addition, our data coherently reached a conclusion that pyrimidine deprivation mediated by GLDC inhibition/depletion could amplify the antiviral response of type I IFN and ISGs and suppress viral replication, which reinforced the link between pyrimidine biosynthesis pathway and antiviral status as consistently demonstrated in other studies (Hoffmann et al , ; Wang et al , ; Cheung et al , ). More recently, a pyrimidine inhibitor identified as a broad‐spectrum antiviral was found to activate RIG‐I (Chung et al , ), an essential cellular sensor to mount innate immune response in influenza virus infection (Loo et al , ). However, the detailed mechanism linking pyrimidine deprivation and the boosted antiviral response definitely requires further study.…”

Transcriptional Regulation of Antiviral Interferon-Stimulated Genes

“…Nucleotides can be synthesized de novo through a series of enzymatic reactions or are recycled through salvage pathways. Interestingly, purine and pyrimidine synthesis inhibitors (such as ribavirin, mycophenolic acid, and brequinar) can efficiently induce ISG expression and exert strong and broad antiviral responses [101][102][103]. However, this process is independent of the classical JAK-STAT cascade, suggesting a non-canonical mechanism that is independent of IFNs [104].…”

Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response

“…The authors further mentioned that no induction of IFNB1 and other antiviral genes was found upon treatment of infected cells with A3 [19]. Another recent report describes a pyrimidine synthesis inhibitor that maintains its activity in Vero cells, and elicits an interferon-independent antiviral state [24]. The combination of both parallel and contrasting findings from different individual research groups led to the postulation that, although multiple different pyrimidine synthesis inhibitors have been reported, explicit underlying mechanisms of action could be at play for different classes of inhibitors, with or without the involvement of interferon at different levels of the pathway.…”