DNA Duplexes with Hydrophobic Modifications Inhibit Fusion between HIV-1 and Cell Membranes |
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| Authors: | Liang Xu Lifeng Cai Xueliang Chen Xifeng Jiang Huihui Chong Baohua Zheng Kun Wang Junlin He Wei Chen Tao Zhang Maosheng Cheng Yuxian He Keliang Liu |
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| Affiliation: | Beijing Institute of Pharmacology and Toxicology, Beijing, Chinaa;School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Chinab;Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Chinac |
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| 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. |
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