title: DNA duplexes with hydrophobic modifications inhibit fusion between HIV-1 and cell membranes.
abstract: Discovery of new drugs for the treatment of AIDS typically possessing unique structures associated with novel mechanisms of action has been of great importance due to the quick drug-resistant mutations of HIV-1 strains. The work presented in this report describes a novel class of DNA duplex-based HIV-1 fusion inhibitors. Hydrophobic groups were introduced into a DNA duplex skeleton either at one end, at both ends, or in the middle. These modified DNA duplexes inhibited fusion between HIV-1 and human cell membranes at micro- or submicromolar concentrations. Respective inhibitors adopted an aptamer pattern instead of a base-pairing interaction pattern. Structure-activity relationship studies of the respective DNA duplexes showed that the rigid and negatively charged DNA skeletons, in addition to the presence of hydrophobic groups, were crucial to the anti-HIV-1 activity of these compounds. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interacted with the primary pocket in the gp41 N-terminal heptad repeat (NHR) instead of interacting with the lipid bilayers.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Lifeng
authors.initials: L
authors.lastname: Cai
authors.forename: Xueliang
authors.initials: X
authors.lastname: Chen
authors.forename: Xifeng
authors.initials: X
authors.lastname: Jiang
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.forename: Baohua
authors.initials: B
authors.lastname: Zheng
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Junlin
authors.initials: J
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
authors.forename: Keliang
authors.initials: K
authors.lastname: Liu
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry* / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
chemical_list: D023581:HIV Fusion Inhibitors; D008051:Lipid Bilayers; D004247:DNA
references.citation: Bioorg Med Chem. 1997 Dec;5(12):2235-43
references.pmid: 9459021
references.citation: J Biol Chem. 2012 Feb 24;287(9):6788-96
references.pmid: 22228771
references.citation: Nucleosides Nucleotides Nucleic Acids. 2010 Oct;29(10):734-47
references.pmid: 20924955
references.citation: Biochem Biophys Res Commun. 2006 Jun 9;344(3):792-7
references.pmid: 16631118
references.citation: AIDS Res Hum Retroviruses. 1990 Nov;6(11):1281-7
references.pmid: 2078409
references.citation: Nucleic Acids Res. 2011 Nov 1;39(20):8984-91
references.pmid: 21771859
references.citation: J Infect. 2009 Dec;59(6):377-86
references.pmid: 19815027
references.citation: Nucleic Acids Res. 2009 May;37(9):3094-109
references.pmid: 19304999
references.citation: Bioorg Med Chem. 1998 Dec;6(12):2469-75
references.pmid: 9925303
references.citation: Antimicrob Agents Chemother. 2007 Jul;51(7):2388-95
references.pmid: 17452484
references.citation: Nucleic Acids Res. 2011 Mar;39(6):2470-81
references.pmid: 21062811
references.citation: Nucleic Acids Symp Ser. 1999;(42):269-70
references.pmid: 10780483
references.citation: Methods. 2011 Jun;54(2):284-94
references.pmid: 21256218
references.citation: Nucleic Acids Res. 2004 Nov 29;32(21):6164-75
references.pmid: 15570067
references.citation: J Biol Chem. 2008 Oct 31;283(44):30376-84
references.pmid: 18662985
references.citation: Bioorg Med Chem Lett. 2000 Oct 2;10(19):2213-6
references.pmid: 11012032
references.citation: Antimicrob Agents Chemother. 2002 Jun;46(6):1896-905
references.pmid: 12019106
references.citation: Bioconjug Chem. 2008 Mar;19(3):607-16
references.pmid: 18254584
references.citation: J Biol Chem. 2000 Jul 14;275(28):21460-7
references.pmid: 10801812
references.citation: J Virol. 2008 Nov;82(22):11129-39
references.pmid: 18768964
references.citation: Antiviral Res. 1996 Jul;31(3):137-48
references.pmid: 8811198
references.citation: FEBS Lett. 2006 Jun 12;580(14):3545-50
references.pmid: 16737697
references.citation: Bioorg Med Chem Lett. 2011 Oct 1;21(19):5762-4
references.pmid: 21873060
references.citation: J Control Release. 2012 Jan 10;157(1):55-63
references.pmid: 21930169
references.citation: Nucleic Acids Res. 2008 Dec;36(22):7124-35
references.pmid: 18996899
references.citation: J Med Chem. 1998 Sep 10;41(19):3655-63
references.pmid: 9733490
references.citation: J Clin Virol. 2009 Jul;45(3):255-8
references.pmid: 19487156
references.citation: Chem Biol. 2012 Jan 27;19(1):60-71
references.pmid: 22284355
references.citation: Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1356-60
references.pmid: 7906414
references.citation: Biophys Chem. 2011 May;155(2-3):82-8
references.pmid: 21435774
references.citation: Bioconjug Chem. 2007 Jul-Aug;18(4):1194-204
references.pmid: 17569499
references.citation: J Biol Chem. 2007 Mar 30;282(13):9612-9620
references.pmid: 17276993
references.citation: Nucleic Acids Res. 1994 Dec 25;22(25):5621-7
references.pmid: 7530843
references.citation: Chem Commun (Camb). 2011 Feb 28;47(8):2363-5
references.pmid: 21305065
references.citation: Trends Biochem Sci. 2005 May;30(5):231-4
references.pmid: 15896739
references.citation: J Biol Chem. 2007 Aug 31;282(35):25631-9
references.pmid: 17616522
references.citation: Biochim Biophys Acta. 2006 Mar;1758(3):290-300
references.pmid: 16337923