title: Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75.
abstract: HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their β-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50=0.826 μg/mL) and high therapeutic index (TI>242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low- to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains.
authors.affiliation: School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Bo-Wen
authors.initials: BW
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Serrao
authors.affiliation: Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Tino W
authors.initials: TW
authors.lastname: Sanchez
authors.affiliation: Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
authors.forename: Liu-Meng
authors.initials: LM
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.affiliation: Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
authors.affiliation: School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China. Electronic address: huiwang@scnu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: yqlong@mail.shcnc.ac.cn.
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D020134:Catalytic Domain; D002867:Chromones / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D055808:Drug Discovery; D005419:Flavonoids / Q000737:chemistry*; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology*; D016761:Oncogene Proteins v-fos / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C000600995:5-hydroxy-3-(4-hydroxyphenyl)-7-morpholino-4H-chromen-4-one; D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D002867:Chromones; D005419:Flavonoids; D019428:HIV Integrase Inhibitors; D009025:Morpholines; D016761:Oncogene Proteins v-fos; C504649:PSIP1 protein, human; D014157:Transcription Factors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: Chelation; Flavonoid; HIV-1 integrase inhibitors; LEDGF/p75; Strand transfer