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
  • 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.