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Il Farmaco

Volume 54, Issues 1–2, January 1999, Pages 26-45
Il Farmaco

Review
Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection

https://doi.org/10.1016/S0014-827X(98)00103-7Get rights and content

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than thirty structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are (or have been) in preclinical and/or clinical development [tivirapine (TIBO R-86183), loviride (α-APA R89439), thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097, DMP 266 (efavirenz), PETT derivatives (trovirdine, PETT-4, PETT-5) and the dichlorophenylthio(pyridyl)imidazole derivative S-1153]. The NNRTIs interact with a specific ‘pocket’ site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, preferably in combination with other anti-HIV agents, are used from the start at sufficiently high concentrations. In vitro, this procedure has been shown to ‘knock-out’ virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations containing NNRTIs, NRTIs and/or PIs may result in an effective viral suppression and ensuing immune recovery. However, this so-called HAART (highly active antiretroviral therapy) may also fail, and this necessitates the design of new and more effective drugs and drug cocktails.

Introduction

The therapy of HIV (human immunodeficiency virus) infections has, since the advent of azidothymidine, been dominated by the 2′,3′-dideoxynucleoside (ddN) derivatives, five of which are now licensed for clinical use: azidothymidine (AZT, zidovudine, Retrovir®), dideoxyinosine (ddI, didanosine, Videx®), dideoxycytidine (ddC, zalcitabine, Hivid®), didehydrodideoxythymidine (d4T, stavudine, Zerit®) and 3′-thiadideoxycytidine (3TC, lamivudine, Epivir®). Four HIV protease inhibitors, i.e. saquinavir (Invirase®), ritonavir (Norvir®), indinavir (Crixivan®) and nelfinavir (Viracept®) have joined the current anti-HIV drug armamentarium [1], [2] and NNRTIs (non-nucleoside reverse transcriptase inhibitors) [3], [4] have recently gained an increasingly important role in the therapy of HIV infections. Several NNRTIs have proceeded onto clinical development (i.e. tivirapine, loviride, MKC-442, HBY 097, DMP 266) or are already licensed for clinical use [nevirapine (Viramune®), delavirdine (Rescriptor®)].

The era of the NNRTIs started about a decennium ago with the discovery of 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) [5], [6] and tetrahydroimidazo[4,5,1-jkj][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) [7], [8] as specific HIV-1 inhibitors, targeted at the HIV-1 reverse transcriptase [7], [8], [9], [10]. These compounds excelled by their unique specificity for HIV-1: they were highly active against HIV-1, but inactive against HIV-2 or any other retrovirus, and, furthermore, their antiviral action could be attributed to a specific interaction with the viral reverse transcriptase (RT).

Following the HEPT and TIBO derivatives, nevirapine (BI-RG-587) [11], [12], pyridinone derivatives L-696,229 and L-697,661 [13], [14], and bis(heteroaryl)piperazine (BHAP) derivatives U-88204 and U-90152 [15], [16] were identified as specific HIV-1 inhibitors. In contrast with HEPT and TIBO, which were first found to inhibit HIV-1 replication in cell culture before their target (HIV-1 RT) was unraveled, nevirapine, pyridinone and BHAP were discovered through an HIV-1 RT screening programme before their antiviral activity in cell culture was established.

Following HEPT, TIBO, nevirapine, pyridinone and BHAP, yet other compounds, i.e. TSAO-T (and TSAO-m3T) [17], [18], [19], loviride [α-APA (R89439)] [20], PETT (LY 300046) [21], new derivatives from HEPT [i.e. I-EBU (MKC-442)] [22] and TIBO [i.e. 8-chloro-TIBO (tivirapine, R86183)] [23], and various other compounds were described as specific HIV-1 RT inhibitors, and all these compounds have been collectively referred to as NNRTIs [3], [4] to distinguish them from the ddNs, now also referred to as NRTIs (nucleoside reverse transcriptase inhibitors) [1], [2].

Section snippets

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

To qualify as an NNRTI, the compound should interact specifically with (a non-substrate binding site of) the RT of HIV-1, and inhibit the replication of HIV-1, but not HIV-2 (or any other retrovirus) at a concentration that is significantly lower than the concentration required to affect normal cell viability [3]. The potency and selectivity of the NNRTIs as specific inhibitors of HIV-1 should be evident from the EC50 (50% effective concentration, required to inhibit HIV-1 replication in cell

Conclusion

HIV-1 viremia, the hallmark of HIV infection, is sustained by a highly dynamic process involving continuous rounds of de novo virus replication and cell turnover [147], [148]. Productively infected cells have, on average, a life-span of 2.2 days (half-life+1.6 days) and plasma virions have a mean life-span of 0.3 days (half-life+0.24 days). The average total HIV-1 production is ca. 1010 virions per day, and the minimum duration of the HIV-1 life cycle in vivo is 1.2 days on average [149]. Virus

Acknowledgements

The dedicated editorial assistance of Christiane Callebaut is gratefully acknowledged. E. De Clercq is titular of the Professor P. De Somer Chair for Microbiology at the Katholieke Universiteit Leuven.

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