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
			Jun 20.

			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).

			Author Information
			(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.9b00781 PMID: 31244113

     			                         Tweet       Print