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Human Immunodeficiency Virus-1 Reverse Transcriptase

Introduction

Structure

Mechanism

Inhibition and Drug Design

The reverse transcriptase enzyme is on of several targets for inhibition in the effort to fight HIV infection. Inhibitors for HIV RT can be grouped into two distinct classes; nucleotide RT inhibitors (NRTIs) and non-nucleotide RT inhibitors (NNRTIs). NRTIs function through competitive inhibition mechanism. These molecules are phosphorylated by cellular kinases and as a result mimic the structure of nucleotides. However, unlike actual nucleotides, NRTIs do not posses the 3'-OH group and as a result terminate chain elongation once they are incorporated into the DNA strand by the enzyme. NNRTI's are non-competitive inhibitors that bind to a specific site on the enzyme but not to the active site. These molecules are typically hydrophobic and bind to a hydrophobic pocket on RT that is in close proximity to the active site. There are some NNRTIs that have been found that do not follow this general scheme and bind to alternative locations on the enzyme, these locations vary with each inhibitor. NNRTIs are highly specific and rarely have any effect on more than one strain of HIV. ^[1]