[24] Development of nonnucleoside HIV reverse transcriptase inhibitors

Tj, Tucker; Wc, Lumma; Jc, Culberson

doi:10.1016/s0076-6879(96)75026-7

Cited by 21 publications

(17 citation statements)

References 48 publications

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“…Nucleoside inhibitors function as competitive substrate analogs that prevent RNA chain elongation when incorporated by the viral enzyme, resulting in premature chain termination (2,3). HIV reverse transcriptase non-nucleoside inhibitors bind to a site residing outside the enzyme active site and inhibit catalysis by an allosteric mechanism (4,5). Several putative allosteric binding sites on the surface of HCV NS5B have been suggested based on recent structural studies (6 -8), and several chemical classes of NS5B non-nucleoside inhibitors have been described (7)(8)(9).…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Characterization of Resistance to Non-obligate Chain-terminating Ribonucleoside Analogs That Inhibit Hepatitis C Virus Replication in Vitro

Migliaccio

Tomassini

Carroll

et al. 2003

Journal of Biological Chemistry

315

316

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The urgent need for efficacious drugs to treat chronic hepatitis C virus (HCV) infection requires a concerted effort to develop inhibitors specific for virally encoded enzymes. We demonstrate that 2-C-methyl ribonucleosides are efficient chain-terminating inhibitors of HCV genome replication. Characterization of drug-resistant HCV replicons defined a single S282T mutation within the active site of the viral polymerase that conferred loss of sensitivity to structurally related compounds in both replicon and isolated polymerase assays. Biochemical analyses demonstrated that resistance at the level of the enzyme results from a combination of reduced affinity of the mutant polymerase for the drug and an increased ability to extend the incorporated nucleoside analog. Importantly, the combination of these agents with interferon-␣ results in synergistic inhibition of HCV genome replication in cell culture. Furthermore, 2-C-methyl-substituted ribonucleosides also inhibited replication of genetically related viruses such as bovine diarrhea virus, yellow fever, and West African Nile viruses. These observations, together with the finding that 2-C-methyl-guanosine in particular has a favorable pharmacological profile, suggest that this class of compounds may have broad utility in the treatment of HCV and other flavivirus infections. Hepatitis C virus (HCV)1 is the most common blood-borne infection and a major cause of chronic liver disease and liver transplantation in industrialized countries. The prevalence of HCV infection is estimated to be ϳ5-fold greater than HIV infection and ranges from 1-5% in most developed countries (1). Current therapy is both poorly tolerated and has limited efficacy, with less than 50% response rates among patients infected with the most prevalent virus genotype (1b) (1). Currently approved drugs for the treatment of hepatitis C are interferon-␣ and ribavirin, neither of which appears to act directly on the virus, and their antiviral effects appear to be mediated by multiple, indirect mechanisms. Therefore, there is a need for more efficient and better tolerated anti-HCV agents.The success of antiviral therapies based on chemotherapeutic agents targeting viral polymerases has prompted intense efforts to develop inhibitors of HCV NS5B, the virally encoded RNA-dependent RNA polymerase (RdRp). Studies with HIV reverse transcriptase validate the clinical utility of two distinct classes of viral polymerase inhibitors, nucleoside and non-nucleoside inhibitors. Nucleoside inhibitors function as competitive substrate analogs that prevent RNA chain elongation when incorporated by the viral enzyme, resulting in premature chain termination (2, 3). HIV reverse transcriptase non-nucleoside inhibitors bind to a site residing outside the enzyme active site and inhibit catalysis by an allosteric mechanism (4, 5). Several putative allosteric binding sites on the surface of HCV NS5B have been suggested based on recent structural studies (6 -8), and several chemical classes of NS5B non-nucleoside inhibitors have ...

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Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Characterization of Resistance to Non-obligate Chain-terminating Ribonucleoside Analogs That Inhibit Hepatitis C Virus Replication in Vitro

Migliaccio

Tomassini

Carroll

et al. 2003

Journal of Biological Chemistry

315

316

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“…This review will focus on the recent and most interesting published results. The NNRTIs synthesized before 1996 are covered by reviews by Artico (1996) and Tucker et al (1996). A review focusing on the role of NNRTIs in the therapy of HIV-1 infections has been published by De Clercq (1998a).…”

Section: Introductionmentioning

confidence: 99%

Non-Nucleoside Reverse Transcriptase Inhibitors: The NNRTI Boom

Pedersen

1999

Antivir Chem Chemother

124

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“…NVP is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 (15)(16)(17). If administered as monotherapy, NVP selects for resistant variants within 1 wk, commonly those variants with the K103N and͞or Y181C mutations in reverse transcriptase, which confer cross-resistance to other approved drugs in the NNRTI class (18)(19)(20).…”

mentioning

confidence: 99%

Persistence of nevirapine-resistant HIV-1 in women after single-dose nevirapine therapy for prevention of maternal-to-fetal HIV-1 transmission

Palmer

Boltz

Martinson

et al. 2006

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

137

114

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Single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission of HIV-1 can select nevirapine (NVP)-resistant variants, but the frequency, duration, and clinical significance of this resistance is not well defined. We used a sensitive allele-specific PCR assay to assess the emergence and persistence of NVPresistant variants in plasma samples from 22 women with HIV-1 subtype C infection who participated in a study of sdNVP for prevention of mother-to-child transmission of HIV-1. The women were categorized into three groups on the basis of detection of NVP resistance by standard genotype analysis. Group 1 (n ‫؍‬ 6) had NVP resistance detected at 2 and 6 mo after sdNVP, but not at 12 mo. Group 2 (n ‫؍‬ 9) had NVP resistance detected at 2 mo, but not 6 mo. Group 3 (n ‫؍‬ 7) had no NVP resistance detected at any time point. Allele-specific PCR analysis for the two most common NVP resistance mutations (K103N and Y181C) detected NVP-resistant variants in most (16 of 21) samples that were negative for NVP resistance by standard genotype, at levels ranging from 0.1% to 20% 1 yr after treatment. The frequency of NVP-resistant mutations decreased over time, but persisted above predose levels for more than 1 yr in >23% of the women. These findings highlight the urgent need for studies assessing the impact of sdNVP on the efficacy of subsequent antiretroviral therapy containing NVP or other nonnucleoside reverse transcriptase inhibitors.allele-specific PCR ͉ resistance ͉ low-frequency mutants T he treatment of pregnant women with antiretroviral therapy, in combination with zidovudine chemoprophylaxis administered to newborns, has dramatically reduced vertical transmission of HIV in developed countries (1-5). However, perinatal transmission of HIV-1 remains a major problem in developing countries because of limited access to antiretroviral therapy (6-8). In this latter setting, the simple regimen of maternal single-dose intrapartum nevirapine (NVP) and single-dose NVP (sdNVP) for the newborn reduces the risk of mother-to-child HIV-1 transmission (MTCT) by 41% through age 18 mo (9). Moreover, sdNVP has been demonstrated to be more effective than zidovudine chemoprophylaxis alone, and to be equivalent to NVP plus zidovudine in preventing MTCT (9-12). The efficacy of sdNVP in preventing MTCT is attributed to its potent antiviral activity, rapid absorption, placental transfer, and long half-life (13, 14). As a result, its use has been recommended by the World Health Organization as one of several options to reduce MTCT in resource-limited countries [Joint UNAIDS͞WHO press release (2000) (WHO, Geneva)].NVP is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 (15-17). If administered as monotherapy, NVP selects for resistant variants within 1 wk, commonly those variants with the K103N and͞or Y181C mutations in reverse transcriptase, which confer cross-resistance to other approved drugs in the NNRTI class (18)(19)(20). The K103N mutation appears to have little effect on the replicative capacity o...

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[24] Development of nonnucleoside HIV reverse transcriptase inhibitors

Cited by 21 publications

References 48 publications

Characterization of Resistance to Non-obligate Chain-terminating Ribonucleoside Analogs That Inhibit Hepatitis C Virus Replication in Vitro

Characterization of Resistance to Non-obligate Chain-terminating Ribonucleoside Analogs That Inhibit Hepatitis C Virus Replication in Vitro

Non-Nucleoside Reverse Transcriptase Inhibitors: The NNRTI Boom

Persistence of nevirapine-resistant HIV-1 in women after single-dose nevirapine therapy for prevention of maternal-to-fetal HIV-1 transmission

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