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Journal of Biochemistry Advance Access originally published online on August 19, 2008
Journal of Biochemistry 2008 144(5):581-589; doi:10.1093/jb/mvn104
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© 2008 The Japanese Biochemical Society

Inhibition of Human Immunodeficiency Virus Type 1 Replication by Blocking I{kappa}B Kinase with Noraristeromycin

Kaori Asamitsu1, Tsuyoshi Yamaguchi2, Kenji Nakata1,3, Yurina Hibi1, Ann-Florence B. Victoriano1, Kenichi Imai1, Kikuo Onozaki3, Yukio Kitade2 and Takashi Okamoto1,*

1Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601; 2Department of Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193; and 3Department of Molecular Health Sciences, Nagoya City University Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan

*To whom correspondence should be addressed. Tel: +81-52-853-8205, Fax: +81-52-859-1235, E-mail: tokamoto{at}med.nagoya-cu.ac.jp

Received May 4, 2008; Accepted August 12, 2008


  Abstract

Nuclear factor {kappa}B (NF-{kappa}B) is one of the critical transcription factors in inflammatory responses and replication of viruses such as human immunodeficiency virus (HIV). In fact, it has been demonstrated that various NF-{kappa}B inhibitors could block HIV replication. To explore more potent NF-{kappa}B inhibitors, we focused on carbocyclic adenine nucleosides that had been reported to have anti-inflammatory effects. We synthesized 15 carbocyclic adenine nucleoside compounds and examined their effects on the NF-{kappa}B-dependent gene expression using HEK293 cell line. Among these compounds, noraristeromycin (NAM) exhibited the most potent inhibitory effect on the NF-{kappa}B activity under the non-cytotoxic concentrations. NAM-inhibited I{kappa}B{alpha} phosphorylation and degradation upon stimulation of cells with tumour necrosis factor-{alpha} (TNF-{alpha}). In addition, NAM prevented p65 phoshorylation. These findings suggested that both I{kappa}B kinase-{alpha} (IKK-{alpha}) and -β were targeted by NAM. Interestingly, in vitro kinase assay revealed that NAM inhibited the kinase activity of IKK-{alpha} more potently than that of IKK-β. When we treated the cell lines, OM10.1 and Molt4/IIIB, in which HIV-1 is latently and chronically infected, we found a strong suppressive effect of NAM on HIV-1 viral replication upon stimulation with TNF-{alpha}.

Key Words: NF-{kappa}B, IKK, noraristreromycin, phosphorylation, transcription

Abbreviations: ACHP, 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine; AZT, 3'-azido-3'-deoxythymidine; cPA, 9-[(1S,3R)-cis-cyclopentan-3-ol]adenine; CREB, cAMP-responsive element binding protein; HIV, human immunodeficiency virus; IKK, I{kappa}B kinase; NAM, noraristeromycin; NF-{kappa}B, nuclear factor {kappa}B; TNF-{alpha}, tumour necrosis factor {alpha}


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