Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep31819
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Funding
- European Union Seventh Framework Program (FP7) under SILVER grant agreement [260644]
- BELSPO (IUAP-BELVIR)
- Spanish CICYT [SAF2012-39760-C02-01]
- Fund for Scientific Research, Flanders (FWO)
- Doctoral Research Training Program Francisco Jose de Caldas from Colombia [494-2009]
- ERACOL scholarship
- JAE-predoctoral fellowship - CSIC
- FSE (Fondo Social Europeo)
- EUVIRNA [264286]
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The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3] triazolo[4,5-d]pyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.
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