Exploiting Structurally Diverse Nucleoside Analogs as Probes of Reverse Transcription Complexes

Authors: Rausch, Jason W.¹; J. Le Grice, Stuart F.¹

Source: Current HIV Research, Volume 5, Number 1, January 2007 , pp. 11-22(12)

Publisher: Bentham Science Publishers

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Abstract:

The emergence of drug-resistant HIV-1 strains presents a challenge for the design of new drugs. Targeting host cell factors involved in the regulation of HIV-1 replication might be one way to overcome the resistance of HIV-1 to anti-viral agents. Our recent studies identified protein phosphatase-1 (PP1) as an important regulator of HIV-1 transcription. Transcription of HIV-1 genes is activated by HIV-1 Tat protein that induces phosphorylation of the Cterminal domain of RNA polymerase-II by CDK9/cyclin T1. We have shown that HIV-1 Tat binds PP1 in vitro; targets PP1 to the nucleus; and that Tat interaction with PP1 is important for HIV-1 transcription. In this review, we discuss two potential targets of PP1 in Tat-induced HIV-1 transcription: the C-terminal domain of RNA polymerase-II and CDK9. We also present a computer model of Tat-PP1 complex that might be useful for future drug design in anti-HIV- 1 therapeutics.

Keywords: central termination sequence (CTS); HIV-1 RT; RNA/DNA hybrid; equine infectious anemia virus (EIAV); Locked Nucleic Acid

Document Type: Research article

DOI: 10.2174/157016207779316332

Affiliations: 1: RT Biochemistry Section,HIV Drug Resistance Program, National Cancer Institute at Frederick, Frederick MD21702, USA.

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