What is the mechanism of action of nonnucleoside reverse transcriptase inhibitors (NNRTIs) in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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HIV reverse transcriptase is a heterodimer composed of 2 subunits (p66 and p51). [27] NNRTIs bind the p66 subunit at a hydrophobic pocket distant from the active site of the enzyme. This noncompetitive binding induces a conformational change in the enzyme that alters the active site and limits its activity. [27]

Etravirine differs from first-generation NNRTIs in its ability to bind at this site despite the presence of some mutations that limit the efficacy of first-generation agents. It is a highly flexible molecule that is able to rotate within the binding site to allow multiple binding conformations. [28]

All four NNRTIs exhibit activity against HIV-1 isolates. In vitro studies have shown that etravirine also has activity against HIV-2. [29]

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