title: D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75.
abstract: Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. In this work, we reported that a benzoic acid derivative, 4-[(5-bromo-4-{[2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,3-thiazolidin-5-ylidene]methyl}-2-ethoxyphenoxy)methyl]benzoic acid (D77) could potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution thus exhibiting antiretroviral activity. Molecular docking with site-directed mutagenesis analysis and surface plasmon resonance (SPR) binding assays has clarified possible binding mode of D77 against HIV-1 integrase. As the firstly discovered small molecular compound targeting HIV-1 integrase interaction with LEDGF/p75, D77 might supply useful structural information for further anti-HIV agent discovery.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Du
authors.forename: Yaxue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Liumeng
authors.initials: L
authors.lastname: Yang
authors.forename: Yongtang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D019817:Benzoic Acid / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019427:HIV Integrase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D016296:Mutagenesis; D020283:Photoreceptors, Microbial / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
chemical_list: C531217:4-((5-bromo-4-((2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,3-thiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)methyl)benzoic acid; D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D001565:Benzoates; D019428:HIV Integrase Inhibitors; C504649:PSIP1 protein, human; D020283:Photoreceptors, Microbial; D045162:Thiazolidinediones; D014157:Transcription Factors; C050162:photoactive yellow protein, Bacteria; D019817:Benzoic Acid; D019427:HIV Integrase