Identification of a novel type of small molecule inhibitor against HIV-1
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Here we report a new chemical inhibitor against HIV-1 with anovel structure and mode of action. The inhibitor, designatedas A1836, inhibited HIV-1 replication and virus productionwith a 50% inhibitory concentration (IC50) of 2.0 μM in anMT-4 cell-based and cytopathic protection antiviral assay, whileits 50% cytotoxic concentration (CC50) was much higher than50 μM. Examination of the effect of A1836 on in vitro HIV-1reverse transcriptase (RT) and integrase showed that neitherwere molecular targets of A1836. The characterization andre-infection assay of the HIV-1 virions generated in the presenceof A1836 showed that the synthesis of early RT productsin the cells infected with the virions was inhibited dose-dependently,due in part to abnormal protein formation withinthe virions, thus resulting in an impaired infectivity. These resultssuggest that A1836 might be a novel candidate for the developmentof a new type of HIV-1 inhibitor.
Abstract
Here we report a new chemical inhibitor against HIV-1 with anovel structure and mode of action. The inhibitor, designatedas A1836, inhibited HIV-1 replication and virus productionwith a 50% inhibitory concentration (IC50) of 2.0 μM in anMT-4 cell-based and cytopathic protection antiviral assay, whileits 50% cytotoxic concentration (CC50) was much higher than50 μM. Examination of the effect of A1836 on in vitro HIV-1reverse transcriptase (RT) and integrase showed that neitherwere molecular targets of A1836. The characterization andre-infection assay of the HIV-1 virions generated in the presenceof A1836 showed that the synthesis of early RT productsin the cells infected with the virions was inhibited dose-dependently,due in part to abnormal protein formation withinthe virions, thus resulting in an impaired infectivity. These resultssuggest that A1836 might be a novel candidate for the developmentof a new type of HIV-1 inhibitor.
참고문헌 (16)
- De Clercq E, "HIV inhibitors targeted at the reverse transcriptase", AIDS Res Hum Retroviruses, 8, pp.119~134 (1992)
- Molla A, "Recent developments in HIV protease inhibitor therapy", Antiviral Res, 39, pp.1~23 (1998)
- Ingale KB, "HIV-1 integrase inhibitors:a review of their chemical development", Antivir Chem Chemother, 22, pp.95~105 (2011)
- Ryser HJ, "Progress in targeting HIV-1 entry", Drug Discov Today, 10, pp.1085~1094 (2005)
- Mehellou Y, "Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go?", J Med Chem, 53, pp.521~538 (2010)
- Flexner C, "HIV drug development: the next 25years", Nat Rev Drug Discov, 6, pp.959~966 (2007)
- Condra JH, "In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors", Nature, 374, pp.569~571 (1995)
- Freed EO, "HIV-1 gag proteins: diverse functions in the virus life cycle", Virology, 251, pp.1~15 (1998)
- Domagala JM, "A new class of anti-HIV-1 agents targeted toward the nucleocapsid protein NCp7: the 2, 2'-dithiobisbenzamides", Bioorg Med Chem, 5, pp.569~579 (1997)
- Srivastava P, "Optimization of unique, uncharged thioesters as inhibitors of HIV replication", Bioorg Med Chem, 12, pp.6437~6450 (2004)
- Ong EB, "Vipirin, a coumarin-based HIV-1 Vpr inhibitor, interacts with a hydrophobic region of VPR", J Biol Chem, 286, pp.14049~14056 (2011)
- Dubé M, "Modulation of HIV-1 host interaction: role of the Vpu accessory protein", Retrovirology, 7, pp.144~ (2010)
- Li ZY, "Progression in the study of HIV-1 Vif and related inhibitors", Yao Xue Xue Bao, 45, pp.684~693 (2010)
- Hyeok Sang Kwon, "Identification of anti-HIV and anti-Reverse Transcriptase activity from Tetracera scandens", BMB Reports, 45(3), pp.165~170 (2012), 생화학분자생물학회
- Hayashi S, "Adenallene and cytallene : acyclic-nucleoside analogues that inhibit replication and cytopathic effect of human immunodeficiency virus in vitro", Proc Natl Acad Sci U S A, 85, pp.6127~6131 (1988)
- Forshey BM, "Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication", J Virol, 76, pp.5667~5677 (2002)