Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Reverse Transcriptase Inhibitors”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 649 records · Page 36Linked to original sources
PubMed1992

[Reverse transcriptase inhibitors and the therapy of HIV infection].

Azidothymidine (retrovir) and didesoxyinosine, which represent nucleoside agents, are major remedies in the treatment of HIV infection and acquired immunodeficiency syndrome (AIDS). The paper describes the molecular mechanism of their action. It implicates that triphosphates of these nucleosides selectively suppress the activity of reverse transcriptase (RNA-dependent DNA polymerase) of HIV by a termination mechanism. This results in effective inhibition of HIV reproduction and recovery of lymphocyte count and yields marked therapeutical benefits. The new generation anti-HIV agents are nucleoside-based phosphonates which were discovered by Russian investigators in 1987. The agents having a significant anti-HIV activity are low toxic. Emphasis is made on combined therapy of HIV infection, which holds much promise.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Quantitative structure-activity relationships and comparative molecular field analysis of TIBO derivatised HIV-1 reverse transcriptase inhibitors.

Quantitative structure-activity relationships (QSAR) and Comparative Molecular Field Analysis (CoMFA) have been applied in order to explain the structural requirements of HIV-1 reverse transcriptase (HIV-1 RT) inhibitory activity of TIBO derivatives on the MT-4 cells. The best QSAR model is satisfactory in both statistical significance and predictive ability. The derived structural descriptors indicate the importance of electronic contributions toward the HIV-1 RT inhibition of this class of compounds. However, it could not reveal any hydrophobic influence because of high collinearity between C2 and log P variables. In order to cope with steric interaction in the correlation, 3D-QSAR was performed using CoMFA. The obtained CoMFA model shows high predictive ability, rcv2 = 0.771, and clearly demonstrates its potential in the steric feature of the molecules through contour maps, explaining a majority (81.8%) of the variance in the data. Consequently, these results can be useful in identifying the structural requirements of TIBO derivatives and helpful for better understanding the HIV-1 RT inhibition. Eventually, they provide a beneficial basis to design new and more potent inhibitors of HIV-1 RT.

Benzodiazepines↗
PubMed1997

Quantitative structure-activity relationship studies on some anti-human-immunodeficiency-virus-1 (anti-HIV-1) drugs: viral reverse transcriptase inhibitors.

The anti-HIV-1 activity of some 3-[(benzoxazol-2-ylmethyl)amino]-, 3-[(benzoxazol-2-yl)ethyl]-, 3-[N-(phthalimidomethyl)amino]- and 3-[N-(phthalimido)ethyl]-5-ethyl-6-methyl pyridin-2(1H)-one derivatives, that have been found to elicit their action through the allosteric inhibition of the enzyme viral reverse transcriptase (VRT), have been analysed in relation to the physicochemical properties of the molecules. Significant correlations were obtained between the activity and the hydrophobic and electronic constants of substituents and van der Waals' volume of the linker chain. Based on these findings the mechanism of action of these drugs is discussed.

Anti-HIV Agents↗
PubMed1992

Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors.

Certain bisheteroarylpiperazines (BHAPs) directly inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and block the spread of infection to susceptible populations of cells. At a 1 microM concentration three analogs, U-87201, U-88204, and U-89674, inhibited the replication of HIV-1 in MT-2 cells by 83, 100, and 93%, respectively. At the same concentration, U-88204 completely inhibited replication of primary HIV-1 isolates in peripheral blood mononuclear cells. Replication of 3'-azido-2',3'-dideoxythymidine (AZT)-resistant strains of HIV-1 was also inhibited by U-88204. When MT-2 cells that were lytically infected with HIV-1 were mixed with uninfected MT-2 cells, U-88204 provided complete protection to the uninfected cells. Integrated proviral DNA sequences were not detected by the polymerase chain reaction technique in this culture after 15 days in the presence of drug. The resultant healthy cell culture was subsequently maintained without drug with no evidence of latent proviral DNA. Serial passage of a laboratory strain and a primary isolate of HIV-1 in cell culture in the presence of increasing concentrations of U-88204 yielded virus populations which were at least 100-fold resistant to the drug. These resistant viruses also showed cross-resistance to the pyridinone class of nonnucleoside inhibitors but were sensitive to AZT. Analysis of the nucleotide sequence of resistant viruses revealed mutations at conserved regions of the reverse transcriptase (RT) gene. The results presented here suggest the therapeutic potential of U-88204 in the combination therapy for HIV-1 infection.

Cell Line↗
PubMed2003

Synthesis and HIV-1 reverse transcriptase inhibitor activity of some 2,5,6-substituted benzoxazole, benzimidazole, benzothiazole and oxazolo(4,5-b)pyridine derivatives.

In this study, the synthesis of some benzoxazoles and their analogues were described and their antiviral activities were studied together with the previously synthesized 2,5,6-trisubstituted benzoxazole, benzothiazole, benzimidazole and oxazolo(4,5-b)pyridine derivatives. The reverse transcriptase (RT) inhibitory activity of these compounds was determined using a commercial kit and assay system which utilizes the scintillation proximity assay principle. The results are concentration at which the compound inhibits RT activity by 50%). The compounds inhibited the in vitro binding of thymidine to the RT enzyme exhibiting IC50 values between 6.3 x 10(5) mumol/l-0.34 mumol/l and their activities were compared to some standard drugs such as 3'-azido-2',3'-dideoxythymidine triphosphate and dideoxythymidine triphosphate.

Benzimidazoles↗
PubMed2000

Non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis and biological evaluation of novel quinoxalinylethylpyridylthioureas as potent antiviral agents.

New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyridylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopathogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inhibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, showed inhibitory activity against wild-type RT as well as against mutant RTs containing the single amino acid substitutions L1001, K103N, V106A, Y1811 and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluoropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQXPT). In cell-based assays on different cell lines and on human monocyte-macrophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a promising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral activity with zidovudine.

Amino Acid Substitution↗
PubMed1996

Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor.

In summary, DLV has been well-tolerated in > 1,000 HIV-1 infected patients. Skin rash is the most prevalent medical event associated with DLV therapy. The rash can be successfully dosed through or rechallenged in > 85% of patients. The pharmacokinetics are non-linear as DLV is metabolized primarily by cytochrome P4503A in the liver. Serum levels of DLV +/- 10 microM can easily be achieved in most HIV-1 patients, which are 100 fold above the in vitro IC90 activity. In clinical trials, DLV inhibits viral replication as demonstrated by positive surrogate marker responses (CD4 counts, P24 antigen concentration, PMBC and plasma virus titers, and plasma HIV RNA concentration). Susceptibility of HIV-1 strains to DLV decrease over time in a majority of subjects in which virus can be cultured. However, HIV strains from about 80% of subjects had a DLV IC50 < 10 microM (the trough DLV concentration in plasma) throughout the Upjohn trial. In HIV strains from about 20% of subjects, susceptibility to DLV remained unchanged in the first 8 months of DLV combination therapy, or HIV-1 was not recovered at all or most timepoints. In contrast, development of resistance to nevirapine or L-697,661 monotherapy or combination therapy with ZDV has occurred in the first eight weeks of therapy. The most common genotypic mutations seen to date are K103N and P236L. The clinical significance of the phenotypic, genotypic and surrogate marker changes associated with DLV remain to be elucidated. The surrogate marker responses in clinical trials suggest that DLV has clinical synergy with ZDV +/- ddI as evidenced by a better and more sustained surrogate marker response when a subject is sensitive to or naive to the nucleoside RTI combined with DLV. Future therapy with DLV will likely be in combination with one or more nucleoside or non-nucleoside RTIs, protease inhibitors and/or immunomodulatory agents.

Antiviral Agents↗
PubMed2006

The HIV-1 reverse transcriptase mutants G190S and G190A, which confer resistance to non-nucleoside reverse transcriptase inhibitors, demonstrate reductions in RNase H activity and DNA synthesis from tRNA(Lys, 3) that correlate with reductions in replication efficiency.

We evaluated the replication efficiency of the HIV reverse transcriptase (RT) mutants K103N, G190A, and G190S, which confer resistance to the non-nucleoside RT inhibitor efavirenz, using growth competition assays in cell culture. In the absence of efavirenz, the fitness hierarchy was G190S < G190A < K103N < wild-type. The fitness reduction of G190S relative to K103N was less evident at high efavirenz concentrations, although K103N still replicated more efficiently. Efficiency of RNase H cleavage and RNA-dependent DNA synthesis from tRNA(Lys, 3) correlated with relative fitness, in biochemical studies of mutant RTs. Presteady state and steady state polymerization assays using DNA primers detected no abnormalities. This work is consistent with previous studies demonstrating that initiation of viral DNA synthesis is reduced in mutants with slowed RNase H cleavage, and suggests that both abnormalities contribute to the replication defect of these mutants. It also suggests that high concentrations of efavirenz are unlikely to favor the selection of G190S clinically.

Amino Acid Substitution↗
PubMed2005

Synthesis of 5'-triphosphate mimics (P3Ms) of 3'-azido-3',5'-dideoxythymidine and 3',5'-dideoxy-5'-difluoromethylenethymidine as HIV-1 reverse transcriptase inhibitors.

3'-Azido-3',5-dideoxythymidine 5'-phosphonate and 3',5'-dideoxy-5'-difluoromethylenethymidine 5'-phosphonate were prepared by multistep syntheses. The nucleoside 5'-phosphonates were converted to their triphosphates and triphosphate mimics (P3Ms) containing beta,gamma-difluoromethylene, beta,gamma-dichloromethylene, or beta,gamma-imodo by condensation with pyrophosphate or pyrophosphate mimics, respectively. Inhibition of HIV-1 reverse transcriptase by the nucleoside P3Ms is briefly discussed.

Dideoxynucleotides↗