PubMed Journals: J Med Chem
Source: PMID: 31244113⇦⇨ J Med Chem. 2019 Jul 11;62(13):6346-6362.
⇩ doi: 10.1021/acs.jmedchem.9b00781. Epub 2019
Design, Synthesis, and Anti-RNA Virus Activity
of 6'-Fluorinated-Aristeromycin Analogues.
Yoon JS(1), Kim G(1)(2), Jarhad DB(1), Kim
HR(1), Shin YS(1), Qu S(1)(3), Sahu PK(4),
Kim HO(4), Lee HW(4), Wang SB(5), Kong YJ(5),
Chang TS(1)(5), Ogando NS(6), Kovacikova
K(6), Snijder EJ(6), Posthuma CC(6), van
Hemert MJ(6), Jeong LS(1).
(1) Research Institute of Pharmaceutical
Sciences, College of Pharmacy,
Seoul National University, Seoul 151-742,
(2) College of Pharmacy and Research Institute
of Drug Development, Chonnam National University,
Gwangju 500-757, Korea.
(3) College of Pharmaceutical Engineering,
Henan University of Animal Husbandry and
Economy, Zhengzhou, 450046, China.
(4) Future Medicine Co., Ltd., Seoul 06665,
(5) College of Pharmacy, Ewha Womans University,
Seoul 120-750, Korea.
(6) Department of Medical Microbiology,
Leiden University Medical Center, Albinusdreef
2, 2333ZA Leiden, The Netherlands.
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 N6-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 ∼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.
DOI: 10.1021/acs.jmedchem.9b00781PMID: 31244113⇧TweetPrint