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PubMedDate not supplied

Animal lentivirus replication and reverse transcriptase inhibitors.

We summarize the pathogenesis of animal lentiviruses (visna-maedi virus, caprine arthritis and encephalitis virus, and equine infectious anemia virus), which have raised considerable interest since the discovery of human lentiviruses. The human lentiviruses possess structural, genetic, and clinical properties similar to those of animal lentiviruses. We describe the different mechanisms of and the principal work on reverse transcriptase inhibitors of animal lentiviruses, such as HPA-23, phosphonoformate, or 2',3'-dideoxynucleosides. Animal viruses of this family may serve as models for infection with human lentiviruses such as human immunodeficiency virus, the etiologic agent of AIDS.

Animals↗

PubMed2006

2'-Deoxy-4'-C-ethynyl-2-fluoroadenosine: a nucleoside reverse transcriptase inhibitor with highly potent activity against all HIV-1 strains, favorable toxic profiles and stability in plasma.

A working hypothesis to solve the critical problems of existing HAART was proposed. The study based on the hypothesis proved the validity of the hypothesis and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoro-adenosine (4'Ed2FA), a nucleoside reverse transcriptase inhibitor (NRTI) with highly potent activity against all HIV-1 strains, very favourable toxic profiles, and stability in plasma.

Animals↗

PubMed2004

In vivo dynamics of the 103N mutation following the withdrawal of non-nucleoside reverse transcriptase inhibitors in HIV-infected patients: preliminary results.

Due to the preferential selection of the fittest HIV mutants, drug-resistant variants are often overgrown by wild-type virus after treatment interruption. Our objective was to investigate the dynamics of the 103N mutation (which usually does not reduce HIV fitness) following the withdrawal of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Patients who were found to have the 103N mutation at or after failure of a NNRTI were selected from an observational database. Two groups of patients were identified: one which continued antiretroviral treatment without NNRTIs (group A) and one which discontinued all anti-retrovirals after failure of an NNRTI (group B). Genotype was obtained by direct sequencing of the replicating plasma virus. Sixty-two subjects tested between July 1998 and December 2002 were included in the analysis, 39 in group A and 23 in group B. At the time of the first resistance test, median (IQR) CD4+ T-lymphocytes and HIV-RNA were 269 (150-449) cells/microL and 25,000 (9,600-83,300) copies/mL. In 31 (50%), 30 (48%), and one case (2%), the 103N mutation was selected by nevirapine, efavirenz, and by delavirdine, respectively. A total of 149 tests were analyzed, with a median (IQR) of 2 (2-3) tests/patient. The median (IQR) interval between failure of NNRTIs and the last resistance test was 11 (5-22) months. Overall, a reversion to wild-type at position 103 was observed in 23/62 (37%) subjects, 14/39 (36%) in group A and 9/23 (39%) in group B. In group A, 14/23 (61%) patients tested within 12 months, 10/16 (63%) of those tested between 12 and 24 months, and 12/14 (86%) of those tested beyond 24 months from NNRTI discontinuation had the 103N mutation. In group B, 14/20 (70%) patients tested within 12 months, 3/4 (75%) of those tested between 12 and 24 months, and none out of two tested beyond 24 months from NNRTI discontinuation had the 103N mutation. In conclusion, following NNRTI discontinuation, in the majority of patients HIV variants carrying the 103N mutation are not overgrown for long by wild-type quasispecies at this position. This suggests that the 103N mutation per se influences minimally the viral fitness in vivo.

Alkynes↗

PubMed2002

Concurrent analysis of nucleoside reverse transcriptase inhibitors in a pool of endogenous nucleosides by short-end injection-capillary electrochromatography on a beta-cyclodextrin-bonded stationary phase.

As part of our on-going study of the analysis of anti-human immunodeficiency virus (HIV) nucleosides, a capillary electrochromatography (CEC) method has been developed for the concurrent analysis of nucleoside HIV reverse transcriptase inhibitors (NRTIs) in a pool of endogenous nucleosides. Up to now, beta-cyclodextrin-bonded silica stationary phases have mainly been dedicated to the separation of enantiomers; however, these polysaccharides can be also be used in achiral way. This work aims at showing how CEC performed on a beta-cyclodextrin-bonded silica stationary phase can be used to concurrently resolve zidovudine (AZT), lamivudine (3TC), didanosine (ddA) and its administrated form (ddI), stavudine (d4T) and hivid (ddC) in a mixture of adenosine (A), cytidine (C), guanosine (G), thymidine (T) and uridine (U). The influence of several parameters (pH buffer, ionic strength, acetonitrile content, temperature and voltage) on both the retention times and the retention factors has been investigated using the short-end injection technique to achieve baseline separation in a short-time analysis before quantitation. Moreover, the retention factors of the charged solutes in short-end injection-CEC were calculated using theoretically derived equations, allowing for the actual voltage drop in the packed section of the semipacked CEC capillary.

Acetonitriles↗

PubMed2003

A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors.

OBJECTIVE: We have shown that HIV-1 clade C variants contain a valine codon 106 polymorphism (GTG) that facilitates a V106M transition (GTG<--ATG) after selection with efavirenz (EFV). This study evaluates the prevalence of V106 (GTG) and 106M (ATG) codons in clinical isolates as well as the effects of V106M on resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI). METHODS: Genotypic analysis ascertained sequence diversity at codon 106, including both valine polymorphisms (GTA and GTG) and the V106A (GCA) and V106M (ATG) resistance-conferring mutations in B (n = 440) and non-B (n = 84) clinical isolates. Cell-based phenotypic assays were performed to determine the effects of V106M and V106A on levels of resistance to EFV, nevirapine and delavirdine. RESULTS: Most subtype B isolates harbored GTA (valine) at codon 106 (97% of cases) while the GTG (valine) polymorphism was generally present in clade C viruses (94% of cases). Under conditions of EFV but not nevirapine or delavirdine pressure (n = 8) in tissue culture, clade C isolates developed the V106M mutation (GTG<--ATG), conferring high-level (100-1000-fold) cross-resistance to all NNRTI. Generation of V106M recombinant viruses by site-directed mutagenesis confirmed the ability of V106M to confer NNRTI cross-resistance. This mutation also developed in three of six EFV-treated patients harboring clade C infections. In current genotypic interpretative reports (including 15 algorithmic databases), V106A is listed as an nevirapine-specific mutation while V106M is not recognized. CONCLUSIONS: V106M may be a signature mutation in clade C patients treated with EFV and may have the potential to confer high-level multi-NNRTI resistance.

Alkynes↗

PubMed2005

The nonnucleoside reverse transcriptase inhibitor UC-781 inhibits human immunodeficiency virus type 1 infection of human cervical tissue and dissemination by migratory cells.

Heterosexual transmission of human immunodeficiency virus remains the major route of transmission worldwide; thus, there is an urgent need for additional prevention strategies, particularly those that could be controlled by women. Using cellular and tissue explant models, we have evaluated the potential activity of thiocarboxanilide nonnucleoside analogue reverse transcriptase inhibitor UC-781 as a vaginal microbicide. We were able to demonstrate a potent dose-dependent effect against R5 and X4 infections of T cells. In human cervical explant cultures, UC-781 was not only able to inhibit direct infection of mucosal tissue but was able to prevent dissemination of virus by migratory cells. UC-781 formulated into a carbopol gel (0.1%) retained significant activity against both direct tissue infection and transinfection mediated by migratory cells. Furthermore, UC-781 demonstrated prolonged inhibitory effects able to prevent both localized and disseminated infections up to 6 days post compound treatment. Additional studies were carried out to determine the concentration of compound that might be required to block a primary infection within draining lymph nodes. While a greater dose of compound was required to inhibit both X4 and R5 infections of lymphoid versus cervical explants, this was equivalent to a 1:3,000 dilution of the 0.1% formulation. Furthermore, a 2-h exposure to the compound prevented infection of lymphoid tissue when challenged up to 2 days later. The prolonged protection observed following pretreatment of both genital and lymphoid tissues with UC-781 suggests that this class of inhibitors may have unique advantages over other classes of potential microbicide candidates.

Acrylic Resins↗

PubMedDate not supplied

Pyridazines 82. Synthesis of pyridazino [3,4-b][1,5]benzodiazepin-5-ones and their biological evaluation as non-nucleoside HIV reverse transcriptase inhibitors.

Starting from 3,6-dichloro-N-(2-chloro-5-nitrophenyl)-pyridazine-4-carboxamide (7) a series of 6,11-dialkylated pyridazino- [3,4-b][1,5]benzodiazepin-5-ones with a 3-chloro-8-nitro, 8-amino, 8-acetylamino, or 8-chloro substitution pattern was prepared via N-alkyl-3-alkylamino-6-chloro-N-(2-chloro-5-nitrophenyl) -pyridazine-4-carboxamides. The new compounds were screened as non-nucleoside reverse transcriptase inhibitors. The influence of the substitution pattern in compounds 10-13 on inhibitory potency is discussed.

Anti-HIV Agents↗

PubMed2001

The role of non-nucleoside reverse transcriptase inhibitors in children with HIV-1 infection.

Over 1.4 million of the worlds' children are infected with HIV-1, mostly acquired in the perinatal period. Antiviral therapeutic options for children with HIV-1 infection have lagged behind those for infected adults. However, we now know that prevention of perinatal HIV-1 transmission to children is possible and that combination therapy for the management of infected children is efficacious. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are developing a more prominent role in combination therapy regimens, particularly as alternatives to protease inhibitors. They also have a role in preventing perinatal transmission, where it has been shown that only 2 doses of the NNRTI nevirapine can significantly reduce mother-to-child transmission of HIV-1. This has major therapeutic implications, particularly in areas where combination therapy is not readily available. Palatable paediatric formulations of NNRTIs are available or are being developed. Whilst pharmacokinetic data regarding the use of antiretrovirals in children remain scarce, published clinical trials have demonstrated the efficacy of NNRTIs when used as part of combination regimens in the management of HIV-1 infected children. The toxicity profile of NNRTIs is relatively favourable; however, severe skin rash, hepatotoxicity and central nervous system adverse effects with various NNRTIs can lead to treatment cessation. The development of class resistance with single step mutations in the reverse transcriptase gene remains a major therapeutic problem with this class of antiretrovirals. Novel NNRTIs under development are of interest either because of improved pharmacodynamics, reduced toxicity profiles or because of action against NNRTI-mutation containing resistant virus. There are no data available yet on the use of these drugs in the paediatric population.

Acquired Immunodeficiency Syndrome↗

PubMed2006

2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, is highly potent against all human immunodeficiency viruses type 1 and has low toxicity.

An idea to use 4'-C-substituted-2'-deoxynucleoside derivatives was proposed based on a working hypothesis to solve the problems of existing acquired immune deficiency syndrome chemotherapy (highly active antiretroviral therapy). Subsequent studies have successfully proved the validity of the idea and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, which is highly potent to all human immunodeficiency viruses type 1 (HIV-1s) including multidrug-resistant HIV-1 and has a low toxicity.

Animals↗

PubMed1998

Synthesis of a non-nucleoside reverse transcriptase inhibitor in the alkenyldiarylmethane (ADAM) series with optimized potency and therapeutic index.

A novel alkenyldiarylmethane (ADAM) analog has been synthesized with enhanced potency as an anti-HIV agent. The new compound (ADAM II) inhibits the cytopathic effect of HIV-1RF in CEM-SS cells with an EC50 of 13 nM, while it shows cytotoxicity with a CC50 of 31.6 microM, providing a therapeutic index of 2430. ADAM II is a non-nucleoside reverse transcriptase inhibitor, displaying an IC50 of 0.3 microM with poly(rC) oligo(dG) as the template/primer.

Anti-HIV Agents↗

PubMed2000

Synthesis and antiviral activity of 4-benzyl pyridinone derivatives as potent and selective non-nucleoside human immunodeficiency virus type 1 reverse transcriptase inhibitors.

Several 4-benzyl analogues of 5-ethyl-6-methyl-4-(phenylthio)pyridin-2(1H)-ones were synthesized and evaluated for their anti-HIV-l activities. Key transformations include metalation at the 4-C-position of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5) and its coupling with benzyl bromide or benzaldehyde derivatives. Biological studies revealed that some of the new 4-benzylpyridinones show potent HIV-1 specific reverse transcriptase inhibitory properties. Compounds 14, 19, and 27, which inhibit the replication of HIV-1 in CEM-SS cells, with IC(50) values ranging from 0.2 to 6 nM are the most active compounds in this series. Biochemical studies showed that compound 27 strongly inhibited the activity of a recombinant HIV-1 RT. Moreover, the infectivity of isolated HIV-1 particles was severely decreased after exposure to compound 27. Although cross resistance is frequently observed between non-nucleoside reverse transcriptase inhibitors, compound 27 was capable of inhibiting a virus resistant to nevirapine with an IC(50) of 40 nM.

Anti-HIV Agents↗

PubMed2004

New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections.

Despite the availability of 20 approved anti-retroviral drugs for the treatment of HIV infection, there is still a need for new anti-retrovirals to improve convenience, reduce toxicity and, of particular importance, to provide activity against the growing number of drug-resistant HIV strains. A new generation of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) is emerging that inhibit HIV-1 strains resistant to the NNRTIs that are prescribed today, and which provide a higher genetic barrier for resistance development than do their predecessors. Of several NNRTIs that are in preclinical and clinical development, two agents, capravirine and TMC125, have shown promise in early clinical trials. The persistent and systematic study of the capacity of HIV to evolve under drug pressure, combined with basic studies in the mode of action of NNRTIs, can provide new weapons in the fight against AIDS.

Anti-HIV Agents↗

PubMed2005

The role of breast cancer resistance protein (BCRP/ABCG2) in cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors.

Treatment of HIV-1-infected patients with anti-retroviral agents is not always successful due to the emergence of resistant HIV-1 mutants with reduced susceptibility to the agents. However, factors other than viral mutation may also contribute to treatment failure. It has been demonstrated that the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp/ABCB1) is a key determinant of oral bioavailability of HIV-1 protease inhibitors and their penetration of the central nervous system. More recently, we have found that the expression of breast cancer resistance protein (BCRP/ABCG2) in a CD4+ T-cell line confers cellular resistance to nucleoside reverse transcriptase inhibitors (NRTIs). The anti-HIV-1 activity of the NRTI zidovudine (AZT) was significantly diminished through the reduction of its metabolite levels in MT-4 cells which express high levels of BCRP. Moreover, the BCRP-specific inhibitor fumitremorgin C could completely restore the cytotoxicity of AZT and intracellular levels of its metabolites in BCRP-expressing cells. Thus, BCRP is considered to be a cellular factor that modulates the anti-HIV-1 activity of NRTIs.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed1995

Nucleoside reverse transcriptase inhibitors and resistance of human immunodeficiency virus type 1.

Drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) emerge during long-term treatment with nucleoside reverse transcriptase inhibitors, such as zidovudine. The clinical significance of in vitro drug resistance to zidovudine has been difficult to determine. However, in a virologic analysis of baseline specimens from the AIDS Clinical Trials Group (ACTG) 116B/117 study, high-level zidovudine resistance, defined as an IC50 of > or = 1 microM at study entry, was significantly associated with clinical disease progression. High-level zidovudine resistance also was an independent predictor of death as an end point, although this finding does not imply a direct causal effect. Duration and cumulative dose of prior zidovudine therapy did not predict clinical disease progression. More potent antiretroviral agents are needed that can be used in combination to achieve more complete virus suppression and to reduce the selection of drug-resistant HIV-1 mutants.

Clinical Trials as Topic↗

PubMed2006

Potency of stampidine against multi-nucleoside reverse transcriptase inhibitor resistant human immunodeficiency viruses.

The in vitro potency of stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) was examined against 8 clinical non-B subtype HIV-1 isolates with resistance to stavudine (STV, d4T), adefovir and tenofovir, 19 clinical zidovudine-resistant HIV-1 isolates, and 6 recombinant HIV-1 clones with multi-resistance against nucleoside reverse transcriptase inhibitors. Stampidine exhibited potent anti-HIV activity against each one of these 33 HIV-1 isolates with subnanomolar to nanomolar IC50 values.

Anti-HIV Agents↗

PubMed2005

The pharmacology of antiretroviral nucleoside and nucleotide reverse transcriptase inhibitors: implications for once-daily dosing.

The trend toward once-daily dosing in HIV antiretroviral therapy is based on the association between adherence, treatment outcome, and patient preferences. Patients prefer simpler treatments, fewer pills, less frequent dosing, and no food restrictions. When a regimen meets a patient's preferences, the patient is more likely to be adherent, and with good adherence, the regimen is more likely to be effective. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have been a prime focus for developing once-daily therapies primarily because they form the backbone of most current regimens. Within the NRTI class, however, drugs differ in their pharmacokinetic properties, such as plasma and intracellular half-lives, and thus in their suitability for once-daily dosing. For example, newer NRTIs, such as tenofovir and emtricitabine, combine longer plasma half-lives with longer intracellular half-lives, prolonging exposure and the period of pharmacologic activity. Of equal importance, the clinical impact of systemic and intracellular interactions between concomitant drugs defines which once-daily drugs may be combined in once-daily regimens. To construct simplified and effective therapies for individual patients, clinicians require an understanding of the plasma and intracellular pharmacokinetic properties of NRTIs and how these properties determine a drug's appropriateness for once-daily dosing and placement within a once-daily regimen.

Drug Administration Schedule↗

PubMed1996

5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepines (PBTDs): a novel class of non-nucleoside reverse transcriptase inhibitors.

With the aim of developing novel inhibitors of human immunodeficiency virus, various derivatives (10-17) related to 5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepine (PBTD) were prepared and tested in vitro. The title tricyclic derivatives were obtained by intramolecular cyclization of the open-chain intermediate arylpyrrylsulfones, followed by N-alkylation at position 10. Among test derivatives some 10-alkyl-5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepin-11(10H)-one-5,5-dioxides were found to exert potent and specific activity against HIV-1. In particular, 7-chloro derivatives 11i and j showed a potency comparable to that of nevirapine. However, when the chloro atom was shifted to the 8 position, the related products were scarcely active or totally inactive. Replacement of the pyrrole with pyrrolidine led to inactive products and the reduction of SO2 to S strongly diminished the antiviral potency. PBTD derivatives active in cell cultures were also inhibitory to the recombinant HIV-1 RT in enzyme assays, thus allowing the conclusion that PBTDs are a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Anti-HIV Agents↗

PubMed2000

Resistance against reverse transcriptase inhibitors.

The response to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients is limited by the emergence of drug resistance. This resistance is a consequence of the high rate of HIV mutation, the high rate of viral replication (especially when potent multidrug therapies are not used or taken reliably), and the selective effect of these drugs, which favors emergence of mutations that can establish clinical drug resistance. The introduction of highly active antiretroviral therapy (HAART), which typically includes at least 2 nucleoside reverse transcriptase inhibitors (RTIs) and a protease inhibitor or a nonnucleoside RTI, for most treatment-naive patients results in a reduction of viral load below the limit of detection determined by currently available HIV RNA assays. It is this marked reduction that results in durable viral suppression, usually only possible by the simultaneous use of 3 or 4 drugs. The RTI components of HAART are crucial for these benefits of combination therapy. Specific amino acid changes are associated with resistance to several RTIs, but new mutation complexes have been observed that can confer broad cross-resistance within this class. Genotypic and phenotypic resistance assays to measure drug resistance are being developed, but refinements in both methodology and our ability to interpret results of these assays are necessary before they are introduced into widespread clinical use.

Anti-HIV Agents↗