What can be Expected from Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in the Treatment of Human Immunodeficiency Virus Type 1 (HIV-1) Infections?

Clercq, Erik De

doi:10.1002/(sici)1099-1654(199606)6:2<97::aid-rmv168>3.0.co;2-4

Cited by 60 publications

(16 citation statements)

References 136 publications

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“…NNRTIs may also be useful as part of a combination anti-HIV strategy with a highly potent NNRTI and additional anti-HIV-1 agents in therapy-naive patients. The potential for the therapeutic use of the NNRTIs in patients has recently been reviewed (19,20). Clinical results reported for nevirapine as a component of a three-drug regimen in patients has highlighted the possible benefits from the development of additional novel or more potent NNRTIs (13).…”

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confidence: 99%

SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

Buckheit

Watson

Fliakas-Boltz

et al. 2001

Antimicrob Agents Chemother

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confidence: 99%

SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

Buckheit

Watson

Fliakas-Boltz

et al. 2001

Antimicrob Agents Chemother

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“…Despite the structural diversity seen in this group of inhibitors, X-ray crystallography studies of HIV-1 RT complexed with a number of different NNRTIs have shown all of these compounds to bind to a single allosteric site, approximately 10 Å from the polymerase catalytic site (13,21). This binding site, which is predominantly hydrophobic, is located in the p66 palm domain of the p66/p51 heterodimer between the ␤-sheet comprising ␤4, ␤7, and ␤8 and the sheet comprising ␤9, ␤10, and ␤11 (21).…”

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Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1

Szczech

Furman

Painter

et al. 2000

Antimicrob Agents Chemother

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Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [ 14 C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.

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“…The NNIs now comprise a very large number of chemically diverse (but largely hydrophobic) compounds, which are subdivided into groups based on their chemical structures. From early examples {e.g., 1-(2-hydroxyethoxymethyl-6-(phenylthio)thymine (HEPT) (4), tetrahydroimidazo- [4,5,l-jk] [1,4]-benzodiazepin-2(1H)-one (TIBO) (5), and nevirapine (6)} to the recent example of alkenyldiarylmethanes (7), more than 30 groups of NNIs have been identified (8). These compounds can be very potent inhibitors of RT, with low toxicity and favorable pharmacokinetic properties.…”

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“…However, the emergence of resistant viral populations, often within days or weeks, seriously compromises their potential therapeutic efficacy. Resistance studies suggest that the NNIs share a common mode of action, binding at a single site that is distinct from the polymerase catalytic site (8). Mutations that confer resistance to one NNI often confer cross-resistance to many other inhibitors [such as the Lys-103-Asn and Tyr-181-Cys mutations (9-11)] and so interest has focused on those compounds that retain pronounced activity against mutant RTs or that have a unique resistance profile.…”

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Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor

Esnouf

Ren

Hopkins

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

180

171

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The The reverse transcriptase (RT; EC 2.7.7.49) of human immunodeficiency virus (HIV) is a multifunctional enzyme critical to the viral life cycle. It is also without a homologue in eukaryotic systems, and thus is an attractive target for anti-HIV therapies. Several RT inhibitors that act as DNA chainterminating analogues of the natural nucleosides have been used to control HIV infection, such as AZT, ddI, ddC, d4T and 3TC (1). However, the emergence of resistant virus populations and significant adverse reactions (2, 3) led to extensive efforts to identify new RT inhibitors.The search for novel RT inhibitors rapidly identified the nonnucleoside inhibitors (NNIs), compounds that are typically HIV-1 specific. The NNIs now comprise a very large number of chemically diverse (but largely hydrophobic) compounds, which are subdivided into groups based on their chemical structures. From early examples {e.g., 1-(2-hydroxyethoxymethyl-6-(phenylthio)thymine (HEPT) (4), tetrahydroimidazo-[4,5,l-jk][1,4]-benzodiazepin-2(1H)-one (TIBO) (5), and nevirapine (6)} to the recent example of alkenyldiarylmethanes (7), more than 30 groups of NNIs have been identified (8). These compounds can be very potent inhibitors of RT, with low toxicity and favorable pharmacokinetic properties. However, the emergence of resistant viral populations, often within days or weeks, seriously compromises their potential therapeutic efficacy. Resistance studies suggest that the NNIs share a common mode of action, binding at a single site that is distinct from the polymerase catalytic site (8). Mutations that confer resistance to one NNI often confer cross-resistance to many other inhibitors [such as the Lys-103-Asn and Tyr-181-Cys mutations (9-11)] and so interest has focused on those compounds that retain pronounced activity against mutant RTs or that have a unique resistance profile.The first structure determination for RT [in complex with the NNI nevirapine at 3.5-Å resolution (12)] has been followed by structures of complexes with other NNIs (13-17), a complex with double-stranded DNA (18), and structures of the unliganded . The structures we have determined to 2.2-Å resolution for RT in complex with NNIs (13) represent the clearest models of RT to date; hence, we use the secondary structure nomenclature of these descriptions. RT is a heterodimer, one subunit (p66) comprises 560 residues and all enzymatic activity of the heterodimer is associated with residues in this subunit. The second chain (p51) comprises the initial 440 residues of the p66 subunit. RT is composed of nine domains (12), named fingers, palm, thumb, connection, and RNase H in the p66, with the p51 containing only the first four of these. The domains of the p66 subunit form a binding groove for the polynucleotide substrate, at the bottom of which lie the aspartyl residues implicated in polymerase activity.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ''advertisement'' in accordance with 18 U....

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What can be Expected from Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in the Treatment of Human Immunodeficiency Virus Type 1 (HIV-1) Infections?

Cited by 60 publications

References 136 publications

SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1

Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor

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