Current Topics in Medicinal Chemistry

Allen B. Reitz
Fox Chase Chemical Diversity Center, Inc.
Doylestown, PA
USA

Back

Biochemical and Mechanistic Basis for the Activity of Nucleoside Analogue Inhibitors of HIV Reverse Transcriptase

Author(s): George R. Painter, Merrick R. Almond, Shuli Mao and Dennis C. Liotta

Affiliation: Chimerix, Inc., 5007Southpark Dr., Suite 200, Durham, NC 27713, USA

Keywords: nucleoside analogue inhibitors, hiv reverse transcriptase, reverse transcriptase, bireactant-biproduct mechanism, lamivudine, coviracil

Abstract:

HIV encodes an RNA directed DNA polymerase (reverse transcriptase, RT) that is an essential enzyme in the viral replication cycle. This enzyme catalyzes the synthesis of double stranded proviral DNA from single stranded genomic RNA via a bireactant-biproduct mechanism. The functional enzyme purified from virus particles is a complex consisting of two polypeptides of molecular weight 66,000 and 51,000. Two of the four classes of currently approved anti-HIV drugs, the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs), act by inhibiting this enzyme. In this review each step of DNA synthesis catalyzed by the RT is described and the mechanism of inhibition of catalysis and termination of DNA synthesis by NRTIs is detailed. The individual steps in the catalytic cycle and the effects that the NRTIs have on them have been examined using transient kinetic analysis. The impact of stereoisomerism and resistance mutations on the rate of NRTI triphosphate incorporation (kpol), binding in the catalytic complex (Kd) and the overall efficiency of incorporation (kpol / Kd) are summarized for lamivudine, coviracil and zalcitabine. The results provide insight into the molecular forces and structural features that make these molecules effective inhibitors.

Reprint ePrint Rights & PermissionsPrintExport

Article Details

VOLUME: 4
ISSUE: 10
Page: [1035 - 1044]
Pages: 10
DOI: 10.2174/1568026043388358