Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 1 de 1
Add filters

Document Type
Year range
PLoS Pathog ; 18(9): e1010832, 2022 09.
Article in English | MEDLINE | ID: covidwho-2039448


There is an outstanding need for broadly acting antiviral drugs to combat emerging viral diseases. Here, we report that thiopurines inhibit the replication of the betacoronaviruses HCoV-OC43 and SARS-CoV-2. 6-Thioguanine (6-TG) disrupted early stages of infection, limiting accumulation of full-length viral genomes, subgenomic RNAs and structural proteins. In ectopic expression models, we observed that 6-TG increased the electrophoretic mobility of Spike from diverse betacoronaviruses, matching the effects of enzymatic removal of N-linked oligosaccharides from Spike in vitro. SARS-CoV-2 virus-like particles (VLPs) harvested from 6-TG-treated cells were deficient in Spike. 6-TG treatment had a similar effect on production of lentiviruses pseudotyped with SARS-CoV-2 Spike, yielding pseudoviruses deficient in Spike and unable to infect ACE2-expressing cells. Together, these findings from complementary ectopic expression and infection models strongly indicate that defective Spike trafficking and processing is an outcome of 6-TG treatment. Using biochemical and genetic approaches we demonstrated that 6-TG is a pro-drug that must be converted to the nucleotide form by hypoxanthine phosphoribosyltransferase 1 (HPRT1) to achieve antiviral activity. This nucleotide form has been shown to inhibit small GTPases Rac1, RhoA, and CDC42; however, we observed that selective chemical inhibitors of these GTPases had no effect on Spike processing or accumulation. By contrast, the broad GTPase agonist ML099 countered the effects of 6-TG, suggesting that the antiviral activity of 6-TG requires the targeting of an unknown GTPase. Overall, these findings suggest that small GTPases are promising targets for host-targeted antivirals.

COVID-19 , Monomeric GTP-Binding Proteins , Prodrugs , Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Humans , Hypoxanthine Phosphoribosyltransferase/metabolism , Monomeric GTP-Binding Proteins/metabolism , Nucleotides/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Thioguanine , Virion/metabolism