title: Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro.
abstract: Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC(50)s ranging from 0.03 to 6.92 nM) and HIV-2 (EC(50)s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Rui-Rui
authors.initials: RR
authors.lastname: Wang
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Yang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Rong-Hua
authors.initials: RH
authors.lastname: Luo
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: You-Mei
authors.initials: YM
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Shao-Xing
authors.initials: SX
authors.lastname: Dai
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; College of Pharmacy and Chemistry, Dali University, Dali, Yunnan, China.
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Cui
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Jing-Fei
authors.initials: JF
authors.lastname: Huang
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Jun-Biao
authors.initials: JB
authors.lastname: Chang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral; D005838:Genotype; D006678:HIV / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D001386:Azides; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D019259:Lamivudine; D054303:HIV Reverse Transcriptase; C540945:azvudine