The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Thomas A Steitz - One of the best experts on this subject based on the ideXlab platform.
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structural basis for potent and broad inhibition of HIV 1 rt by thiophene 3 2 d pyrimidine non nucleoside inhibitors
eLife, 2018Co-Authors: Christophe Pannecouque, Yang Yang, Dongwei Kang, Laura A Nguyen, Zachary B Smithline, Peng Zhan, Xinyong Liu, Thomas A SteitzAbstract:Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV Therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 A resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.
Yang Yang - One of the best experts on this subject based on the ideXlab platform.
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structural basis for potent and broad inhibition of HIV 1 rt by thiophene 3 2 d pyrimidine non nucleoside inhibitors
eLife, 2018Co-Authors: Christophe Pannecouque, Yang Yang, Dongwei Kang, Laura A Nguyen, Zachary B Smithline, Peng Zhan, Xinyong Liu, Thomas A SteitzAbstract:Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV Therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 A resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.
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Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d] pyrimidine non-nucleoside inhibitors
'eLife Sciences Publications Ltd', 2018Co-Authors: Yang Yang, Kang Dongwei, Nguyen, Laura A, Smithline, Zachary B, Pannecouque Christophe, Zhan Peng, Liu Xinyong, Steitz, Thomas AAbstract:Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV Therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.status: publishe
Judith G Levin - One of the best experts on this subject based on the ideXlab platform.
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human immunodeficiency virus type 1 nucleocapsid protein promotes efficient strand transfer and specific viral dna synthesis by inhibiting tar dependent self priming from minus strand strong stop dna
Journal of Virology, 1997Co-Authors: Jianhui Guo, Louis E Henderson, Julian W Bess, Bradley P Kane, Judith G LevinAbstract:During the first strand transfer in reverse transcription, minus-strand strong-stop DNA [(-) SSDNA] is annealed to the 3' end of the acceptor RNA in a reaction mediated by base-pairing between terminal repeat sequences in the RNA and their complement in the DNA. The large stem-loop structure in the repeat region known as TAR could interfere with this annealing reaction. We have developed an in vitro human immunodeficiency virus type 1 (HIV-1) system to investigate the effect of TAR on strand transfer. Mutational analysis demonstrates that the presence of TAR in the donor and acceptor templates inhibits strand transfer and is correlated with extensive synthesis of heterogeneous DNAs formed by self-priming from (-) SSDNA. These DNAs are not precursors to the transfer product. Interestingly, products of self-priming are not detected in HIV-1 endogenous reactions; this suggests that virions contain a component which prevents self-priming. Our results show that the viral nucleocapsid protein (NC), which can destabilize secondary structures, drastically reduces self-priming and dramatically increases the efficiency of strand transfer. In addition, the data suggest that the ability to eliminate self-priming is a general property of NC which is manifested during reverse transcriptase pausing at sites of secondary structure in the template. We conclude that this activity of NC is critical for achieving highly efficient and specific viral DNA synthesis. Our findings raise the possibility that inactivation of NC could provide a new approach for targeting reverse transcription in anti-HIV Therapy.
Christophe Pannecouque - One of the best experts on this subject based on the ideXlab platform.
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structural basis for potent and broad inhibition of HIV 1 rt by thiophene 3 2 d pyrimidine non nucleoside inhibitors
eLife, 2018Co-Authors: Christophe Pannecouque, Yang Yang, Dongwei Kang, Laura A Nguyen, Zachary B Smithline, Peng Zhan, Xinyong Liu, Thomas A SteitzAbstract:Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV Therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 A resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.
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resistance of human immunodeficiency virus type 1 to the high mannose binding agents cyanovirin n and concanavalin a
Journal of Virology, 2005Co-Authors: Myriam Witvrouw, James H Mcmahon, Valery Fikkert, Anke Hantson, Christophe Pannecouque, Leonidas Stamatatos, Anders BolmstedtAbstract:Due to the biological significance of the carbohydrate component of the human immunodeficiency virus type 1 (HIV-1) glycoproteins in viral pathogenesis, the glycosylation step constitutes an attractive target for anti-HIV Therapy. Cyanovirin N (CV-N), which specifically targets the high-mannose (HM) glycans on gp120, has been identified as a potent HIV-1 entry inhibitor. Concanavalin A (ConA) represents another mannose-binding lectin, although it has a lower specificity for HM glycans than that of CV-N. For the present study, we selected CV-N- and ConA-resistant HIV-1 strains in the presence of CV-N and ConA, respectively. Both resistant strains exhibited a variety of mutations eliminating N-linked glycans within gp120. Strains resistant to CV-N or ConA displayed high levels of cross-resistance towards one another. The N-glycan at position 302 was eliminated in both of the lectin-resistant strains. However, the elimination of this glycan alone by site-directed mutagenesis was not sufficient to render HIV-1 resistant to CV-N or ConA, suggesting that HIV-1 needs to mutate several N-glycans to become resistant to these lectins. Both strains also demonstrated clear cross-resistance towards the carbohydrate-dependent monoclonal antibody 2G12. In contrast, the selected strains did not show a reduced susceptibility towards the nonlectin entry inhibitors AMD3100 and enfuvirtide or towards reverse transcriptase or protease inhibitors. Recombination of the mutated gp160 genes of the strains resistant to CV-N or ConA into a wild-type background fully reproduced the (cross-)resistance profiles of the originally selected strains, pointing to the impact of the N-glycan mutations on the phenotypic resistance profiles of both selected strains.
Kenneth A Freedberg - One of the best experts on this subject based on the ideXlab platform.
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use of genotypic resistance testing to guide HIV Therapy clinical impact and cost effectiveness
Annals of Internal Medicine, 2001Co-Authors: Milton C Weinstein, Sue J Goldie, Elena Losina, Calvin J Cohen, John D Baxter, Hong Zhang, April D Kimmel, Kenneth A FreedbergAbstract:Genotypic antiretroviral resistance testing following antiretroviral failure is cost-effective. Primary resistance testing also seems to be reasonably cost-effective and will become more so as the ...
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use of genotypic resistance testing to guide HIV Therapy clinical impact and cost effectiveness
Annals of Internal Medicine, 2001Co-Authors: Milton C Weinstein, Sue J Goldie, Elena Losina, Calvin J Cohen, John D Baxter, Hong Zhang, April D Kimmel, Kenneth A FreedbergAbstract:Background: Genotypic sequencing for drug-resistant strains of HIV can guide the choice of antiretroviral Therapy. Objective: To assess the cost-effectiveness of genotypic resistance testing for patients acquiring drug resistance through failed treatment (secondary resistance) and those infected with resistant virus (primary resistance). Design: Cost-effectiveness analysis with an HIV simulation model incorporating CD4 cell count and HIV RNA level as predictors of disease progression. Data Sources: Published randomized trials and data from the Multicenter AIDS Cohort Study, the national AIDS Cost and Services Utilization Survey, the Red Book, and an institutional cost-accounting system. Target Population: HIV-infected patients in the United States with baseline CD4 counts of 0.250 x 10 9 cells/L. Time Horizon: Lifetime. Perspective: Societal. Interventions: Genotypic resistance testing and clinical judgment, compared with clinical judgment alone, in two contexts: after initial treatment failure (secondary resistance testing) and before initiation of antiretroviral Therapy (primary resistance testing). Outcome Measures: Life expectancy, quality-adjusted life expectancy, and cost-effectiveness in dollars per quality-adjusted life-year (QALY) gained. Results of Base-Case Analysis: Secondary resistance testing increased life expectancy by 3 months, at a cost of $17 900 per QALY gained. The cost-effectiveness of primary resistance testing was $22 300 per QALY gained with a 20% prevalence of primary resistance but increased to $69 000 per QALY gained with 4% prevalence. Results of Sensitivity Analysis: The cost-effectiveness ratio for secondary resistance testing remained under $25 000 per QALY gained, even when effectiveness and cost of testing and antiretroviral Therapy, quality-of-life weights, and discount rate were varied. Conclusions: Genotypic antiretroviral resistance testing following antiretroviral failure is cost-effective. Primary resistance testing also seems to be reasonably cost-effective and will become more so as the prevalence of primary resistance increases.