2. Academic Validation
  3. Design, Synthesis, and Anti-RNA Virus Activity of 6'-Fluorinated-Aristeromycin Analogues

Design, Synthesis, and Anti-RNA Virus Activity of 6'-Fluorinated-Aristeromycin Analogues

  • J Med Chem. 2019 Jul 11;62(13):6346-6362. doi: 10.1021/acs.jmedchem.9b00781.
Ji-Seong Yoon 1,  Gyudong Kim 1 2,  Dnyandev B Jarhad 1,  Hong-Rae Kim 1,  Young-Sup Shin 1,  Shuhao Qu 1 3,  Pramod K Sahu 4,  Hea Ok Kim 4,  Hyuk Woo Lee 4,  Su Bin Wang 5,  Yun Jeong Kong 5,  Tong-Shin Chang 1 5,  Natacha S Ogando 6,  Kristina Kovacikova 6,  Eric J Snijder 6,  Clara C Posthuma 6,  Martijn J van Hemert 6,  Lak Shin Jeong 1
Affiliations

Affiliations

  • 1 Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 151-742 , Korea.
  • 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 , Korea.
  • 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.
PMID: 31244113 DOI: 10.1021/acs.jmedchem.9b00781
Abstract

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.

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