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			PubMed Journals: J Biol Chem

  Source:		PMID: 32094225


    		J Biol Chem. 2020 Feb 24. pii:
     		jbc.AC120.013056. doi:
			10.1074/jbc.AC120.013056. [Epub ahead of
			print]

			The antiviral compound remdesivir potently
			inhibits RNA-dependent RNA polymerase from
			Middle East respiratory syndrome coronavirus.

			Gordon CJ(1), Tchesnokov EP(1), Feng JY(2),
			Porter DP(3), Gotte M(4).

			Author Information
			(1) University of Alberta, Canada.
			(2) Biology, Gilead Sciences, United States.
			(3) Gilead, United States.
			(4) Medical Microbiology and Immunology,
			University of Alberta, Canada.

			Antiviral drugs for managing infections with
			human coronaviruses are not yet approved,
			posing a serious challenge to current global
			efforts aimed at containing the outbreak of
			severe acute respiratory syndrome coronavirus
			2 (SARS-CoV-2). Remdesivir (RDV) is an
			investigational compound with a broad
			spectrum of antiviral activities against RNA
			viruses, including SARS-CoV and
			Middle East respiratory syndrome (MERS-CoV).
			RDV is a nucleotide analog inhibitor of
			RNA-dependent RNA polymerases (RdRps).
			Here, we co-expressed the MERS-CoV
			nonstructural proteins nsp5, nsp7, nsp8, and
			nsp12 (RdRp) in insect cells as a part a
			polyprotein to study the mechanism of inhibition
			of MERS-CoV RdRp by RDV. We initially
			demonstrated that nsp8 and nsp12 form an
			active complex. The triphosphate form of the
			inhibitor (RDV-TP) competes with its natural
			counterpart ATP. Of note, the selectivity value
			for RDV-TP obtained here with a steady-state
			approach suggests that it is more efficiently
			incorporated than ATP and two other
			nucleotide analogues. Once incorporated at
			position i, the inhibitor caused RNA synthesis
			arrest at position i+3. Hence, the likely
			mechanism of action is delayed RNA chain
			termination. The additional three nucleotides
			may protect the inhibitor from excision by the
			viral 3'-5' exonuclease activity. Together, these
			results help to explain the high potency of RDV
			against RNA viruses in cell-based assays.

			Published under license by The American
			Society for Biochemistry and Molecular Biology,
			Inc.

			DOI: 10.1074/jbc.AC120.013056
			PMID: 32094225

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