Non-nucleoside-RT-inhibitors

Synthetic non-nucleoside RT inhibitor (NNRTI) in clinical use Synthetic nucleoside reverse transcriptase inhibitors (NRTIs) in clinical use metabolic conversion to the nucleoside triphosphate (NTP) (via the nucleoside monophosphate (NMP) and diphosphate (NDP)) gives DNA chain termination because of absence of 3 -hydroxyl (Note PMEA yields the phosphonate diphosphate ... 

The ONIOM method, as implemented in the Gaussian03 program package [73], has been proven to be applicable to large molecular systems, where different levels of theory are applied on various parts of the molecular cluster [74,75]. The interactions of non-nucleoside RT inhibitors with the amino acids of the inhibition pocket of the enzyme, and the induced conformational changes, are the results of several sensitive phenomena which need careful and accurate treatment. Calculations of the whole complex, however, is rather difficult because of the large size of the system. Therefore, an approach combining QM/MM or ONIOM methods for such HIV-1... 

The first lead compounds for non-nucleoside reverse transcriptase (RT) inhibitors (NNRTl) were discovered about 15 years ago (Pauwels et al. 1990 Merluzzi et al. 1990 Goldman et al. 1991 De Clercq 1993 Riibsamen-Waigmann et al. 1997). Since then they have become an important ingredient of the dmg combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HlV-1) infections. Starting from the HEPT and TIBO derivatives, numerous classes of compounds have been described as NNRTIs. Four compounds (nevirapine, delavirdine, efavirenz and etravirine) have so far been approved for clinical use and several others are the subject of clinical trials (Balzarini 2004 Stellbrink 2007). 

RT reverse transcriptase, NRTI nucleoside reverse transcriptase inhibitors, NNRTI Non-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... 

The development of antiretroviral therapy has been a major challenge since the discovery of the human inununodeficiency virus (HIV). Early successes with nucleoside and non-nucleoside reverse transcriptase (RT) inhibitors, as well as the development of protease inhibitors have facilitated, in recent years, a highly active antiretroviral therapy (HAART), where a combination of drugs is simultaneously administered. In spite of significant improvements in the morbidity and mortality of HIV-infected patients, the rapid appearance of resistant HIV-variants, as well as adverse effects and high cost of contemporary drugs necessitate the continuous development of independent classes of anti-HIV agents. ... 

Campiani G et al. Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors Past, present, and future perspectives. Curr Pharm Des 2002 8 615-657. 

Experience teaches us that combinations of active compounds offer the most promising perspective - for example, the combination of AZT with 3TC of BioChemPharma (Laval, Quebec, Canada). Currently (2003), there are seven approved entities of nucleoside analogs (NRTIs) and three approved non-nucleosides (NNRTIs) that inhibit reverse transcriptase (RT) by mimicking the structure of DNA building blocks and thus the copy process of RNA into DNA by reverse transcriptase. In addition, five HIV protease inhibitors and one viral fusion inhibitor have been approved. 

NRTIs, which act as a substrate for RT, are not the only means of inhibiting reverse transcriptase. Like any enzyme, inhibitors can also bind allosteric positions away from the active site. An allosteric site on RT has been successfully targeted by drugs, and these drugs are called non-nucleoside reverse transcriptase inhibitors (NNRTIs). The three most frequently prescribed NNRTIs are shown in Figure A.46. 

A number of crystal structures of RT complexed with several non-nucleoside inhibitors have recently been reported [7]. These structures also contain complexes with 1 and 2. All... 

HiV reverse transcriptase (HiV RT) A new generation of non-nucleoside inhibitors against wild-type RT and drug-resistant RT mutants was rationally designed several compounds were found to outperform existing RT drugs. 182... 

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