{"title":"The Establishment of an Antiviral State by Pyrimidine Synthesis Inhibitor is Cell Type-Specific.","authors":"Donghoon Chung","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":91527,"journal":{"name":"Journal of antimicrobial agents","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34655466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-06DOI: 10.4172/2472-1212.1000101
D. Chung
The replication of virus is dependent on the host metabolism; nucleotide precursors for the synthesis of viral genome or viral mRNAs are supplied from the host nucleotides pool. As viral replication requires a massive synthesis of viral mRNA or viral genome, the inhibition of cellular nucleotide synthesis is considered a strategy for broad-spectrum antivirals. Indeed, the inhibition of GTP synthesis showed antiviral effects against many viruses. Mycophenolic acid (MPA) has broad-spectrum antiviral activity and the mechanism is to decrease cellular GTP concentration by inhibiting inosine-5’-monophosphate dehydrogenase (IMPDH), which catalyzes the rate-limiting reaction of de novo GTP biosynthesis [1]. Many IMPDH inhibitors, however, show noticeable cytotoxicity at the effective concentrations, making them less attractive as an antiviral therapeutic [2–5]. On the other hand, pyrimidine synthesis inhibitors are getting more attention as a novel antiviral strategy. Several pyrimidine synthesis inhibitors have been discovered as active hit compounds from high-throughput screenings for antivirals [6–8]. Unlike MPA, these pyrimidine synthesis inhibitors did not show toxicity to the cells at the effective concentrations. Recently, a novel antiviral mechanism was discovered that could interpret the robust antiviral activity of pyrimidine synthesis inhibitors. Marianne et al. has shown that brequinar or DD264, a dihydroorotate dehydrogenase (DHODH) inhibitor, has broad-spectrum antiviral activity and the treatment of the cells with the compounds induced the expression of IFN-stimulated genes (ISGs) that are associated with the antiviral effects [9]. The compound decreased cellular pyrimidine concentration; however, the decrease of pyrimidine concentration was not the main antiviral mechanism. More importantly, the antiviral effect was dependent on the synthesis of new proteins under the control of interferon regulatory transcription factor 1 (IRF1). This finding clearly illustrates how pyrimidine synthesis inhibitors could exert potent broad-spectrum antiviral activity without cytotoxicity unlike MPA. This finding could lead to the development of broad-spectrum antivirals from pyrimidine synthesis inhibitors. In support of the mechanism, leflunomide, an immunosuppressant drug that inhibits DHODH, the fourth enzyme of the pyrimidine biosynthesis (Figure 1), has been reported to have an antiviral effect against several viruses in a clinical study [10]. Figure 1 Brequinar and DHODH, Structure of brequinar (A), and the pyrimidine de novo biosynthesis pathway (B).DHODH is the rate limiting step and inhibited by brequinar. Despite this prominent antiviral effect in vitro, none of the pyrimidine synthesis inhibitors have shown antiviral effect in vivo models using mice [6–8]. For this reason, pyrimidine synthesis inhibition has not been accepted as a viable antiviral strategy. It has been speculated that the concentration of exogenous pyrimidi
{"title":"The Establishment of an Antiviral State by Pyrimidine Synthesis Inhibitor is Cell Type-Specific","authors":"D. Chung","doi":"10.4172/2472-1212.1000101","DOIUrl":"https://doi.org/10.4172/2472-1212.1000101","url":null,"abstract":"The replication of virus is dependent on the host metabolism; nucleotide precursors for the synthesis of viral genome or viral mRNAs are supplied from the host nucleotides pool. As viral replication requires a massive synthesis of viral mRNA or viral genome, the inhibition of cellular nucleotide synthesis is considered a strategy for broad-spectrum antivirals. Indeed, the inhibition of GTP synthesis showed antiviral effects against many viruses. Mycophenolic acid (MPA) has broad-spectrum antiviral activity and the mechanism is to decrease cellular GTP concentration by inhibiting inosine-5’-monophosphate dehydrogenase (IMPDH), which catalyzes the rate-limiting reaction of de novo GTP biosynthesis [1]. Many IMPDH inhibitors, however, show noticeable cytotoxicity at the effective concentrations, making them less attractive as an antiviral therapeutic [2–5]. \u0000 \u0000On the other hand, pyrimidine synthesis inhibitors are getting more attention as a novel antiviral strategy. Several pyrimidine synthesis inhibitors have been discovered as active hit compounds from high-throughput screenings for antivirals [6–8]. Unlike MPA, these pyrimidine synthesis inhibitors did not show toxicity to the cells at the effective concentrations. Recently, a novel antiviral mechanism was discovered that could interpret the robust antiviral activity of pyrimidine synthesis inhibitors. Marianne et al. has shown that brequinar or DD264, a dihydroorotate dehydrogenase (DHODH) inhibitor, has broad-spectrum antiviral activity and the treatment of the cells with the compounds induced the expression of IFN-stimulated genes (ISGs) that are associated with the antiviral effects [9]. The compound decreased cellular pyrimidine concentration; however, the decrease of pyrimidine concentration was not the main antiviral mechanism. More importantly, the antiviral effect was dependent on the synthesis of new proteins under the control of interferon regulatory transcription factor 1 (IRF1). This finding clearly illustrates how pyrimidine synthesis inhibitors could exert potent broad-spectrum antiviral activity without cytotoxicity unlike MPA. This finding could lead to the development of broad-spectrum antivirals from pyrimidine synthesis inhibitors. In support of the mechanism, leflunomide, an immunosuppressant drug that inhibits DHODH, the fourth enzyme of the pyrimidine biosynthesis (Figure 1), has been reported to have an antiviral effect against several viruses in a clinical study [10]. \u0000 \u0000 \u0000 \u0000Figure 1 \u0000 \u0000Brequinar and DHODH, Structure of brequinar (A), and the pyrimidine de novo biosynthesis pathway (B).DHODH is the rate limiting step and inhibited by brequinar. \u0000 \u0000 \u0000 \u0000Despite this prominent antiviral effect in vitro, none of the pyrimidine synthesis inhibitors have shown antiviral effect in vivo models using mice [6–8]. For this reason, pyrimidine synthesis inhibition has not been accepted as a viable antiviral strategy. It has been speculated that the concentration of exogenous pyrimidi","PeriodicalId":91527,"journal":{"name":"Journal of antimicrobial agents","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70317680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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