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			PubMed Journals: J Virol

  Source:		PMID: 30918074


    		J Virol. 2019 Mar 27. pii: JVI.00023-19.
     		doi: 10.1128/JVI.00023-19. [Epub ahead of
			print]

			High-throughput Screening and Identification
			of Potent Broad-spectrum Inhibitors of
			Coronaviruses.

			Shen L(1), Niu J(1), Wang C(2), Huang B(1),
			Wang W(1), Zhu N(1), Deng Y(1), Wang H(1),
			Ye F(1), Cen S(3), Tan W(4).

			Author Information
			(1) NHC Key Laboratory of Biosafety, Ministry
			of Health, National Institute for Viral
			Disease Control and Prevention, China CDC,
			Beijing 102206, China.
			(2) National Institutes for Food and Drug
			Control, Beijing 100050, China.
			(3) Department of Immunology, Institute
			of Medicinal Biotechnology,
			Chinese Academy of Medical Sciences,
			Beijing 100050, China.
			(4) NHC Key Laboratory of Biosafety, Ministry
			of Health, National Institute for Viral
			Disease Control and Prevention, China CDC,
			Beijing 102206, China tanwj28@163.com.

			Coronaviruses (CoVs) act as cross-species
			viruses and have the potential to spread
			rapidly into new host species and cause
			epidemic diseases. Despite the severe public
			health threat of
			severe acute respiratory syndrome coronavirus
			and Middle East respiratory syndrome
			CoV (MERS-CoV), there are currently no drugs
			available for their treatment; therefore,
			broad-spectrum inhibitors of emerging and
			endemic CoVs are urgently needed. To search
			for effective inhibitory agents, we performed
			high-throughput screening (HTS) of a 2,000-compound
			library of approved drugs and pharmacologically
			active compounds using the established genetically
			engineered human CoV OC43 (HCoV-OC43) strain
			expressing Renilla luciferase (rOC43-ns2Del-Rluc)
			and validated the inhibitors using multiple
			genetically distinct CoVs in vitro We screened
			56 hits from the HTS data and validated
			36 compounds in vitro using wild-type HCoV-OC43.
			Furthermore, we identified seven compounds
			(lycorine, emetine, monensin sodium, mycophenolate
			mofeti, mycophenolic acid, phenazopyridine, and
			pyrvinium pamoate) as broad-spectrum inhibitors
			according to their strong inhibition of
			replication by four CoVs in vitro at low-micromolar
			concentrations. Additionally, we found that
			emetine blocked MERS-CoV entry according
			to pseudovirus-entry assays, and that lycorine
			protected BALB/c mice against HCoV-OC43-induced
			lethality by decreasing viral load in the
			central nervous system. This represents the
			first demonstration of in vivo real-time
			bioluminescence imaging to monitor the effect of lycorine
			on the spread and distribution of HCoV-OC43
			in a mouse model. These results offer critical
			information supporting the development of
			an effective therapeutic strategy against
			CoV infection.IMPORTANCE Currently, there is no approved
			therapy to treat coronavirus infection;
			therefore, broad-spectrum inhibitors of
			emerging and endemic CoVs are needed. Based
			on our high-throughput screening assay using
			a compound library, we identified seven
			compounds with broad-spectrum efficacy against
			the replication of four CoVs in vitro Additionally,
			one compound (lycorine) was found to protect
			BALB/c mice against HCoV-OC43-induced lethality
			by decreasing viral load in the central
			nervous system. This inhibitor might offer
			promising therapeutic possibilities for
			combatting novel CoV infections in the future.

			Copyright © 2019 American Society for Microbiology.

			DOI: 10.1128/JVI.00023-19 PMID: 30918074

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