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	Characterization of dengue virus resistance to brequinar in cell culture
	Qing, Min1,2; Zou, Gang1; Wang, Qing-Yin1; Xu, Hao Ying1; Dong, Hongping1; Yuan, Zhiming2; Shi, Pei-Yong1
刊名	Antimicrobial agents and chemotherapy
	2010-09-01
卷号	54期号:9页码:3686-3695
ISSN号	0066-4804
DOI	10.1128/aac.00561-10
通讯作者	Wang, qing-yin(qing_yin.wang@novartis.com)
英文摘要	Brequinar is an inhibitor of dihydroorotate dehydrogenase, an enzyme that is required for de novo pyrimidine biosynthesis. here we report that brequinar has activity against a broad spectrum of viruses. the compound not only inhibits flaviviruses (dengue virus, west nile virus, yellow fever virus, and powassan virus) but also suppresses a plus-strand rna alphavirus (western equine encephalitis virus) and a negative-strand rna rhabdovirus (vesicular stomatitis virus). using dengue virus serotype 2 (denv-2) as a model, we found that brequinar suppressed the viral infection cycle mainly at the step of rna synthesis. supplementing the culture medium with pyrimidines (cytidine or uridine) but not purines (adenine or guanine) could be used to reverse the inhibitory effect of the compound. continuous culturing of denv-2 in the presence of brequinar generated viruses that were partially resistant to the inhibitor. sequencing of the resistant viruses revealed two amino acid mutations: one mutation (m260v) located at a helix in the domain ii of the viral envelope protein and another mutation (e802q) located at the priming loop of the nonstructural protein 5 (ns5) polymerase domain. functional analysis of the mutations suggests that the ns5 mutation exerts resistance through enhancement of polymerase activity. the envelope protein mutation reduced the efficiency of virion assembly/release; however, the mutant virus became less sensitive to brequinar inhibition at the step of virion assembly/release. taken together, the results indicate that (i) brequinar blocks denv rna synthesis through depletion of intracellular pyrimidine pools and (ii) the compound may also exert its antiviral activity through inhibition of virion assembly/release.
WOS关键词	WEST-NILE-VIRUS ; HUMAN DIHYDROOROTATE DEHYDROGENASE ; DE-NOVO SYNTHESIS ; NONSTRUCTURAL PROTEIN ; FLAVIVIRUS RNA ; CRYSTAL-STRUCTURE ; KUNJIN VIRUS ; CDNA-CLONES ; INHIBITION ; REPLICATION
WOS研究方向	Microbiology ; Pharmacology & Pharmacy
WOS类目	Microbiology ; Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC MICROBIOLOGY
WOS记录号	WOS:000281005900023
内容类型	期刊论文
URI标识	http://www.corc.org.cn/handle/1471x/2375696
专题	武汉病毒研究所
通讯作者	Wang, Qing-Yin
作者单位	1.Novartis Inst Trop Dis, Singapore 138670, Singapore 2.Chinese Acad Sci, State Key Lab Virol, Wuhan Inst Virol, Beijing 100864, Peoples R China
推荐引用方式 GB/T 7714	Qing, Min,Zou, Gang,Wang, Qing-Yin,et al. Characterization of dengue virus resistance to brequinar in cell culture[J]. Antimicrobial agents and chemotherapy,2010,54(9):3686-3695.
APA	Qing, Min.,Zou, Gang.,Wang, Qing-Yin.,Xu, Hao Ying.,Dong, Hongping.,...&Shi, Pei-Yong.(2010).Characterization of dengue virus resistance to brequinar in cell culture.Antimicrobial agents and chemotherapy,54(9),3686-3695.
MLA	Qing, Min,et al."Characterization of dengue virus resistance to brequinar in cell culture".Antimicrobial agents and chemotherapy 54.9(2010):3686-3695.

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