期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 13, 页码 6346-6362出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00781
关键词
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资金
- Mid-career Research Program of the National Research Foundation (NRF), Korea [2016R1A2B3010164]
- Ministry of Science, ICT & Future Planning of the National Research Foundation (NRF), Korea [2017M3A9A8032086]
- EU Marie Sklodowska-Curie ETN ANTIVIRALS [642434]
- Marie Curie Actions (MSCA) [642434] Funding Source: Marie Curie Actions (MSCA)
- National Research Foundation of Korea [2016R1A2B3010164, 2017M3A9A8032086] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The 6'-fluorinated aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S-adenosyl-L-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6'-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N-6-methyladenosine analogues 2a-e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a-c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-Difluoroaristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a similar to 2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.
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