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A new class of HIV-1 inhibitors and the target identification via proteomic profiling

文献类型：期刊论文

作者Ge, Ying-Zi1; Zhou, Bin1; Xiao, Ruo-Xuan1; Yuan, Xiao-Jing1; Zhou, Hu1; Xu, Ye-Chun1; Wainberg, Mark A.2; Han, Ying-Shan2; Yue, Jian-Min1
刊名SCIENCE CHINA-CHEMISTRY
出版日期2018-11
卷号61期号:11页码:1430-1439
关键词ergostane-type steroids anti-HIV target identification PKM2
ISSN号1674-7291
DOI10.1007/s11426-018-9283-3
文献子类Article
英文摘要Anti-HIV screening with the MT-4/MTT assay on a focused library of structurally diverse natural products has led to the discovery of a group of steroids with potent activities, which include four new ergostane-type steroids, named amotsterols A-D (1-4), together with two known analogs. Among them, the most potent amotsterol D (4) exhibited anti-HIV activity against wildtype and some clinically relevant multidrug resistant HIV-1 strains. Subsequent studies on its target identification through a proteomic approach found that compound 4 might target PKM2, a rate limiting enzyme of glycolysis, in host cells to restrict HIV replication. The docking model of compound 4 to PKM2 showed that the two hydroxyl groups of 4 form hydrogen bonds with the two parallel Y390 in each subunit of PKM2 separately, and the ring C of 4 is sandwiched between the two parallel aromatic rings of F26. The identified hit compound may have the potential to be further developed as a novel anti-HIV agent. These results demonstrated that an integrated approach, which combines new chemical structures and phenotypic screening with a proteomic approach, could not only identify novel HIV-1 inhibitors, but also elucidate the unknown targets of compound interactions in antiviral drug discovery.
WOS关键词INTEGRASE INHIBITORS ; NATURAL-PRODUCTS ; STABILITY DARTS ; DRUG DISCOVERY ; TRICHILIA-CONNAROIDES ; LIMONOIDS ; STEROLS ; PKM2 ; RESISTANCE ; ACTIVATORS
资助项目National Natural Science Foundation of China[21532007] ; National Natural Science Foundation of China[U1302222] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development" Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020321] ; Canadian Institutes for Health Research (CIHR)[00000000]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000450158400015
出版者SCIENCE PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/279514]  
专题天然药物化学研究室_岳建民课题组
分析化学研究室_周虎课题组
通讯作者Han, Ying-Shan; Yue, Jian-Min
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
2.McGill Univ, Jewish Gen Hosp, AIDS Ctr, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
推荐引用方式
GB/T 7714		 Ge, Ying-Zi,Zhou, Bin,Xiao, Ruo-Xuan,et al. A new class of HIV-1 inhibitors and the target identification via proteomic profiling[J]. SCIENCE CHINA-CHEMISTRY,2018,61(11):1430-1439.
APA Ge, Ying-Zi.,Zhou, Bin.,Xiao, Ruo-Xuan.,Yuan, Xiao-Jing.,Zhou, Hu.,...&Yue, Jian-Min.(2018).A new class of HIV-1 inhibitors and the target identification via proteomic profiling.SCIENCE CHINA-CHEMISTRY,61(11),1430-1439.
MLA Ge, Ying-Zi,et al."A new class of HIV-1 inhibitors and the target identification via proteomic profiling".SCIENCE CHINA-CHEMISTRY 61.11(2018):1430-1439.

入库方式： OAI收割

来源：上海药物研究所

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