NNRTI interactions Nucleoside reverse transcriptase inhibitors

The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was heralded by the discovery of the tetrahydroimidazo[4,5,1 -// .][ 1,4]benzo-diazepin-2(l //)-onc and -thione (TIBO) derivatives (Fig. 7) [58,59] and 1 -(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives (Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59], For the HEPT derivatives it became evident that they also interact specifically with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and E-EBU-dM) had been synthesized that were more active than HEPT itself [62,63]. Following HEPT and TIBO, several other compounds, i.e., nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were... 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

In parallel, non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit RT by a non-competitive binding to an allosteric site closely located to the catalytic site [18]. The short distances separating the allosteric and the binding sites suggest that NNRTIs alter the function of RT and directly disturb the interactions between the nucleotide natural substrates and the active site. 

The prototype compound of this family was the thymine derivative TSAO-T (Figure 2.18). TSAO derivatives were targeted at the HIV-l-encoded reverse transcriptase (RT) with which they interacted at a nonsubstrate binding site. Within the non-nucleoside reverse transcriptase inhibitors (NNRTIs), the TSAO nucleosides occupy a unique position in that they interfered at the interface between the P51 and P66 subunits of RT. A variety of 1,2,3-triazole TSAO derivatives (Figure 2.18) substituted at the 5-position of the triazole moiety were evaluated for their inhibitory effects against HIV-1- and HIV-2-induced cytopathicity in CEM and MT-4 cell cultures. The most active TSAO derivatives were those that contained either iV-ethyl (55) Af-cyclopropyl carbamoyl (56)... 

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