Nucleoside HIV reverse transcriptase

The answer is d. (Katzung, pp 831-832.) Zidovudine competitively inhibits HIV-1 nucleoside reverse transcriptase. It is also incorporated in the growing viral DNA chain to cause termination. Each action requires activation via phosphorylation of cellular enzymes. Zidovudine decreases the rate of clinical disease progression and prolongs survival in HIV-infected patients. 

X. Wang and M. Baba. The role of breast cancer resistance protein (BCRP/ ABCG2) in cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Antivir Chem Chemother. 16 213-216 (2005). 

In the realm of natural product synthesis, Kepler and Rehder utilized the K-R reaction to synthesize ( )-calanolide A (56), a potent non-nucleosidal human irmnunodeficiency virus (HIV-1) specific reverse transcriptase inhibitor. Propiophenone 57 was allowed to react with acetic anhydride in the presence of sodium acetate to afford benzopyranone 58 in 56% yield subsequent deacetylation of 58 gave 59. Flavone 59 was then transformed to ( ) calanolide A (56) over several steps. 

Efavirenz (1) was chosen over compound 2 as a developmental candidate in 1993 based on its better antivirus activities, especially against resistant strains [1, 17]. Efavirenz is the first HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) which was approved by the FDA on September 21, 1998. The original Medicinal Chemistry method to prepare Efavirenz is depicted in Scheme 1.14. 

P. S. Synthesis of a series of 4-(arylethynyl)-6-chloro-4-cydopropyl-3,4-dihydroquinazolin-2(lH)-ones as novel non-nucleoside HIV-1 532 reverse transcriptase inhibitors./. Med. Chem. 

Difluorophenyl derivatives 243 were synthesized and tested in the frame of a SAR study on 1,2,3-Thiadiazole thioacetanihdes as HIV non-nucleoside reverse transcriptase inhibitors. They showed the ability to protect MT-4 cells from viral cytopathogenicity in the low-micromolar range, bnt resulted less active than the chlorinated analogues to be further considered (Fig. 9) [121],... 

Magnus NA, Confalone PN, Storace L (2000) A new asymmetric 1,4-addition method application to the synthesis of the HIV non-nucleoside reverse transcriptase inhibitor DPC 961. Tetrahedron Lett 41 3015-3019... 

There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.11 The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla (Figure 1.1). 

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... 

Cross-resistance In clinical trials, patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. Consider the potential for cross-resistance between abacavir and other NRTIs when choosing new therapeutic regimens in therapy-experienced patients. 

Nearly 40 million people are infected with the human immunodeficiency virus (HIV). Over half of those infected reside in sub-Saharan Africa. Worldwide during 2004, it is estimated that nearly 14,000 people a day were infected. Human immunodeficiency virus type 1 is the primary etiological source for the acquired immunodeficiency syndrome (AIDS). Fortunately, people infected with HIV are leading longer and more productive lives due to the availability of more effective therapies. Better medicines have evolved due to the efforts of scientists worldwide who find targets and compounds that inhibit the virus life-cycle. The current treatment for HIV infection is via a drug cocktail that usually includes a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), and a non-nucleoside reverse transcriptase inhibitor (NNRTI). 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI), launched for the treatment of HIV infection (Figure 8.6). It is currently in Phase III trials for the treatment of hepatitis B virus (HBV) infection. A prodrug of the NRTI alovudine— fosalvudine tidoxil—is currently in Phase II (Figure 8.1). 

Mechanism of Action A non-nucleoside reverse transcriptase inhibitor that binds directly to HlV-1 reverse transcriptase and blocks RNA- and DNA-dependent DNA polymerase activities. Therapeutic Effect Interrupts HIV replication, slowing the progression of HIV infection. 

Mechanism of Action A nucleoside reverse transcriptase inhibitor that inhibits viral DNA synthesis. Therapeutic Effect Prevents replication of HIV-1. 

Brennan TM, Taylor DL, Bridges CG, Leyda JP, Tyms AS. The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442 alone and in combination with other anti-HIV compounds. Antiviral Res 1995 26 173-187. 

After oral administration, abacavir is rapidly absorbed, and its bioavailability is about 83%. Food does not interfere with its absorption, and it is metabolized by alcohol dehydrogenase to 5 -carboxylic acid derivative and to S -glucuronidc by glucuronidation. Abacavir does not affect the cytochrome P-450 system. In combination with other antiretroviral drugs, abacavir is indicated for the treatment of HIV-1 infection. It is more potent than other nucleoside reverse transcriptase inhibitors in reducing HIV plasma concentration and increasing CD4+ count. 

Sluis-Cremer, N., Arion, D., and Parniak, M. A. (2000). Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs). Cell Mol. Life Sci. 57, 1408-1422. 

Efavirenz (DMP 266) (1) is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by the US Food Drug Administration (FDA) for treatment of the acquired immunodeficiency syndrome (AIDS).1 2 3 Inhibition of HIV reverse transcriptase by nucleosides like azidothymidine (AZT) (2) is a proven therapy for delaying the progression to AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents. The recent development of both protease inhibitors and non-nucleoside reverse transcriptase inhibitors offers hope of effective treatment especially when coadministered. 

These drugs are highly selective, noncompetitive inhibitors of HIV-1 reverse transcriptase. They do not interfere with the binding of primer, template, or nucleoside triphosphates. They have no effect on human DNA polymerases. Their major advantage is their lack of effect on the host blood-forming elements, and lack of cross-resistance with nucleoside reverse transcriptase inhibitors. 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS RIBAVIRIN 1. t side-effects, risk of lactic acidosis, peripheral neuropathy, pancreatitis, hepatic decompensation, mitochondrial toxicity and anaemia with didanosine and stavudine 2.1 efficacy of lamivudine 1. Additive side-effects t intracellular activation of didanosine and stavudine 2. J intracellular activation of lamivudine 1. Not recommended. Use with extreme caution monitor lactate, LFTs and amylase closely. Stop co-administration if peripheral neuropathy occurs. Stavudine and didanosine carry a higher risk 2. Monitor HIV RNA levels if they T, review treatment combination... 

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