The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
J W Erickson - One of the best experts on this subject based on the ideXlab platform.
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selection and analysis of human immunodeficiency virus type 1 variants with Increased Resistance to abt 538 a novel protease inhibitor
Journal of Virology, 1995Co-Authors: M Markowitz, D J Kempf, D W Norbeck, T N Bhat, J W EricksonAbstract:Inhibitors of the human immunodeficiency virus protease represent a promising new class of antiretroviral drugs for the treatment of AIDS. We now report the in vitro selection of viral variants with decreased sensitivity to a symmetry-based protease inhibitor, ABT-538, currently being tested in clinical trials. Molecular characterization of the variants shows that an isoleucine-to-valine substitution at position 84 results in a substantial decrease in sensitivity to the drug. Moreover, an additional mutation at position 82, valine to phenylalanine, further decreases viral susceptibility to ABT-538. Three-dimensional analysis of the protease-drug complex provides a structural explanation for the relative drug Resistance induced by these two mutations. These findings emphasize the importance of closely monitoring patients receiving ABT-538 for the emergence of viral Resistance and provide information that may prove useful in designing the next generation of protease inhibitors.
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characterization of human immunodeficiency virus type 1 variants with Increased Resistance to a c2 symmetric protease inhibitor
Journal of Virology, 1994Co-Authors: T Toyoshima, D J Kempf, D W Norbeck, Chihming Chen, N E Wideburg, S K Burt, J W Erickson, M K SinghAbstract:Inhibitors of the human immunodeficiency virus type 1 protease represent a promising class of antiviral drugs for the treatment of AIDS, and several are now in clinical trials. Here, we report the in vitro selection of viral variants with decreased sensitivity to a C2-symmetric protease inhibitor (A-77003). We show that a single amino acid substitution (Arg to Gln or Lys) at position 8 of the protease results in a substantial decrease in the inhibitory activity of the drug on the enzyme and a comparable increase in viral Resistance. These findings, when analyzed by using the three-dimensional structure of the protease-drug complex, provide a strategic guide for the future development of inhibitors of the human immunodeficiency virus type 1 protease.
M K Singh - One of the best experts on this subject based on the ideXlab platform.
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characterization of human immunodeficiency virus type 1 variants with Increased Resistance to a c2 symmetric protease inhibitor
Journal of Virology, 1994Co-Authors: T Toyoshima, D J Kempf, D W Norbeck, Chihming Chen, N E Wideburg, S K Burt, J W Erickson, M K SinghAbstract:Inhibitors of the human immunodeficiency virus type 1 protease represent a promising class of antiviral drugs for the treatment of AIDS, and several are now in clinical trials. Here, we report the in vitro selection of viral variants with decreased sensitivity to a C2-symmetric protease inhibitor (A-77003). We show that a single amino acid substitution (Arg to Gln or Lys) at position 8 of the protease results in a substantial decrease in the inhibitory activity of the drug on the enzyme and a comparable increase in viral Resistance. These findings, when analyzed by using the three-dimensional structure of the protease-drug complex, provide a strategic guide for the future development of inhibitors of the human immunodeficiency virus type 1 protease.
Lawrence Shapiro - One of the best experts on this subject based on the ideXlab platform.
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Increased Resistance of sars cov 2 variant p 1 to antibody neutralization
Cell Host & Microbe, 2021Co-Authors: Pengfei Wang, Ryan G Casner, Manoj S Nair, Maple Wang, Gabriele Cerutti, Lihong Liu, Peter D Kwong, Yaoxing Huang, Lawrence ShapiroAbstract:The emergence of SARS-CoV-2 variants has raised concerns about altered sensitivity to antibody-mediated immunity. The relative Resistance of SARS-CoV-2 variants B.1.1.7 and B.1.351 to antibody neutralization has been recently investigated. We report that another emergent variant from Brazil, P.1, is not only refractory to multiple neutralizing monoclonal antibodies but also more resistant to neutralization by convalescent plasma and vaccinee sera. The magnitude of Resistance is greater for monoclonal antibodies than vaccinee sera and evident with both pseudovirus and authentic P.1 virus. The cryoelectron microscopy structure of a soluble prefusion-stabilized spike reveals that the P.1 trimer adopts exclusively a conformation in which one of the receptor-binding domains is in the "up" position, which is known to facilitate binding to entry receptor ACE2. The functional impact of P.1 mutations thus appears to arise from local changes instead of global conformational alterations. The P.1 variant threatens current antibody therapies but less so protective vaccine efficacy.
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Increased Resistance of sars cov 2 variant p 1 to antibody neutralization
bioRxiv, 2021Co-Authors: Pengfei Wang, Ryan G Casner, Manoj S Nair, Maple Wang, Gabriele Cerutti, Lihong Liu, Peter D Kwong, Yaoxing Huang, Lawrence ShapiroAbstract:The relative Resistance of SARS-CoV-2 variants B.1.1.7 and B.1.351 to antibody neutralization has been described recently. We now report that another emergent variant from Brazil, P.1, is not only refractory to multiple neutralizing monoclonal antibodies, but also more resistant to neutralization by convalescent plasma (3.4 fold) and vaccinee sera (3.8-4.8 fold). The cryo-electron microscopy structure of a soluble prefusion-stabilized spike reveals the P.1 trimer to adopt exclusively a conformation in which one of the receptor-binding domains is in the "up" position, with the functional impact of mutations appearing to arise from local changes instead of global conformational alterations. The P.1 variant threatens current antibody therapies but less so the protective efficacy of our vaccines.
D W Norbeck - One of the best experts on this subject based on the ideXlab platform.
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selection and analysis of human immunodeficiency virus type 1 variants with Increased Resistance to abt 538 a novel protease inhibitor
Journal of Virology, 1995Co-Authors: M Markowitz, D J Kempf, D W Norbeck, T N Bhat, J W EricksonAbstract:Inhibitors of the human immunodeficiency virus protease represent a promising new class of antiretroviral drugs for the treatment of AIDS. We now report the in vitro selection of viral variants with decreased sensitivity to a symmetry-based protease inhibitor, ABT-538, currently being tested in clinical trials. Molecular characterization of the variants shows that an isoleucine-to-valine substitution at position 84 results in a substantial decrease in sensitivity to the drug. Moreover, an additional mutation at position 82, valine to phenylalanine, further decreases viral susceptibility to ABT-538. Three-dimensional analysis of the protease-drug complex provides a structural explanation for the relative drug Resistance induced by these two mutations. These findings emphasize the importance of closely monitoring patients receiving ABT-538 for the emergence of viral Resistance and provide information that may prove useful in designing the next generation of protease inhibitors.
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characterization of human immunodeficiency virus type 1 variants with Increased Resistance to a c2 symmetric protease inhibitor
Journal of Virology, 1994Co-Authors: T Toyoshima, D J Kempf, D W Norbeck, Chihming Chen, N E Wideburg, S K Burt, J W Erickson, M K SinghAbstract:Inhibitors of the human immunodeficiency virus type 1 protease represent a promising class of antiviral drugs for the treatment of AIDS, and several are now in clinical trials. Here, we report the in vitro selection of viral variants with decreased sensitivity to a C2-symmetric protease inhibitor (A-77003). We show that a single amino acid substitution (Arg to Gln or Lys) at position 8 of the protease results in a substantial decrease in the inhibitory activity of the drug on the enzyme and a comparable increase in viral Resistance. These findings, when analyzed by using the three-dimensional structure of the protease-drug complex, provide a strategic guide for the future development of inhibitors of the human immunodeficiency virus type 1 protease.
D J Kempf - One of the best experts on this subject based on the ideXlab platform.
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selection and analysis of human immunodeficiency virus type 1 variants with Increased Resistance to abt 538 a novel protease inhibitor
Journal of Virology, 1995Co-Authors: M Markowitz, D J Kempf, D W Norbeck, T N Bhat, J W EricksonAbstract:Inhibitors of the human immunodeficiency virus protease represent a promising new class of antiretroviral drugs for the treatment of AIDS. We now report the in vitro selection of viral variants with decreased sensitivity to a symmetry-based protease inhibitor, ABT-538, currently being tested in clinical trials. Molecular characterization of the variants shows that an isoleucine-to-valine substitution at position 84 results in a substantial decrease in sensitivity to the drug. Moreover, an additional mutation at position 82, valine to phenylalanine, further decreases viral susceptibility to ABT-538. Three-dimensional analysis of the protease-drug complex provides a structural explanation for the relative drug Resistance induced by these two mutations. These findings emphasize the importance of closely monitoring patients receiving ABT-538 for the emergence of viral Resistance and provide information that may prove useful in designing the next generation of protease inhibitors.
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characterization of human immunodeficiency virus type 1 variants with Increased Resistance to a c2 symmetric protease inhibitor
Journal of Virology, 1994Co-Authors: T Toyoshima, D J Kempf, D W Norbeck, Chihming Chen, N E Wideburg, S K Burt, J W Erickson, M K SinghAbstract:Inhibitors of the human immunodeficiency virus type 1 protease represent a promising class of antiviral drugs for the treatment of AIDS, and several are now in clinical trials. Here, we report the in vitro selection of viral variants with decreased sensitivity to a C2-symmetric protease inhibitor (A-77003). We show that a single amino acid substitution (Arg to Gln or Lys) at position 8 of the protease results in a substantial decrease in the inhibitory activity of the drug on the enzyme and a comparable increase in viral Resistance. These findings, when analyzed by using the three-dimensional structure of the protease-drug complex, provide a strategic guide for the future development of inhibitors of the human immunodeficiency virus type 1 protease.
