The NNRTIs act by binding non-competitively to the RT enzyme (figure 3). The binding causes conformational change in the three-dimensional structure of the enzyme and creates the NNIBP. Binding of NNRTI to HIV-1 RT makes the p66 thumb domain hyper extended because it induces rotamer conformation changes in amino acid residues Tyr-181 and Tyr-188. This affects the catalytic activity of the enzyme and blocks the HIV-1 replication by inhibiting the polymerase active site of the RT's p66 subunit. The global conformational change additionally destabilizes the enzyme on its nucleic acid template and reduces its ability to bind nucleotides. The transcription of the viral RNA is inhibited and therefore the replication rate of the virus reduces. Although the exact molecular mechanism is still hypothetical this has been demonstrated by multiple studies to be the primary mechanism of action.
In addition to this proposed primary mechanism of action it has been shown that the NNRTIs have other mechanisms of action and interfere with various steps in the reverse transcriptase reaction. It has been suggested that the inhibition of reverse transcription by the NNRTIs may be due to effects on the RT Rnase H activity and/or template/primer binding. Some NNRTIs interfere with HIV-1 Gag-Pol polyprotein processing by inhibiting the late stage of HIV-1 replication.
It is important to gain profound understanding of the various mechanism of action of the NNRTIs in order to develop next-generation NNRTIs and for understanding the mechanism of drug resistance.