4.7 Article

Thiopurines inhibit coronavirus Spike protein processing and incorporation into progeny virions

期刊

PLOS PATHOGENS
卷 18, 期 9, 页码 -

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PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1010832

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资金

  1. Canadian Institutes for Health Research (CIHR) [PJT-148727]
  2. Natural Sciences and Engineering Research Council (NSERC) [RGPIN-2016-05083]
  3. Research Nova Scotia [RNS-NHIG2020-1383]
  4. Lung Association of Nova Scotia Legacy Research Grant
  5. Nova Scotia COVID-19 Health Research Coalition Grant
  6. Canadian Institutes of Health Research (CIHR) [OV5-170349, VRI-173022, VS1175531]
  7. Government of Saskatchewan through Innovation Saskatchewan
  8. Ministry of Agriculture
  9. Canada Foundation for Innovation

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Reported the inhibitory effect of thiopurines on the replication of HCoV-OC43 and SARS-CoV-2 coronaviruses, and discovered defective Spike trafficking and processing as a result of 6-TG treatment.
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.

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