Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Various non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been reported to specifically inhibit human immunodeficiency virus type 1 (HIV-1): for example, tetrahydroimidazobenzodiazepinone (TIBO), hydroxyethoxymethylphenylthiothymine (HEPT), dipyridodiazepinone (i.e. nevirapine), pyridinone, bis(heteroaryl)piperazine (BHAP), tert-butyldimethylsilylspiroaminooxathioledioxide (TSAO), α-anilinophenylacetamide (α-APA) and quinoxaline derivatives. These compounds interact allosterically (i.e. non-competitively with respect to the natural substrate (dNTPs)) with a specific non-substrate binding site ‘pocket’ of the HIV-1 reverse transcriptase (RT). The most potent NNRTIs have been found to inhibit HIV-1 replication at nanomolar concentrations. These compounds therefore offer great potential for the treatment of HIV-1 infections. Yet, the virus may rapidly develop resistance to these drugs. The mutations conferring resistance have been mapped at the RT positions 100 (Leu × lle), 103 (Lys × Asn), 106 (Val × Ala), 108 (Val × lle), 138 (Glu × Lys), 179 (Val × Asp), 181 (Tyr × Cys), 188 (Tyr × Cys/His), 190 (Gly × Glu) and 236 (Pro × Leu). However, these mutations do not necessarily lead to cross-resistance among the various NNRTIs, and, in some cases, they have proved to be mutually suppressive. Several strategies could be envisaged to circumvent or prevent the resistance problem: switching from one NNRTI (to which the virus has developed resistance) to another (to which the virus has not developed resistance); combining different RT inhibitors that do not confer cross-resistance, or that may, in fact, even counteract development of resistance to one another; and, using sufficiently high (‘knocking-out’) concentrations of the NNRTIs from the start, so as to completely shut down virus replication and prevent resistance from emerging. NNRTIs differ in several aspects from the 2,3-dideoxynucleoside (ddN) type of RT inhibitors. An obvious strategy to be further pursued in clinical trials is based upon the combination of NNRTIs with ddNs, as such combinations may offer synergistic anti-HIV activity, while reducing the risk or rate of resistance development.