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The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope

OBJECTIVES: This study was designed to identify common HIV-1 mutation complexes affecting the slope of inhibition curve, and to propose a new parameter incorporating both the IC50 and the slope to evaluate phenotypic resistance. METHODS: Utilizing site-directed mutagenesis, we constructed 22 HIV-1 c...

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Autores principales: Chang, Shuai, Zhuang, Daomin, Guo, Wei, Li, Lin, Zhang, Wenfu, Liu, Siyang, Li, Hanping, Liu, Yongjian, Bao, Zuoyi, Han, Jingwan, Song, Hongbin, Li, Jingyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773073/
https://www.ncbi.nlm.nih.gov/pubmed/26930645
http://dx.doi.org/10.1371/journal.pone.0149467
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author Chang, Shuai
Zhuang, Daomin
Guo, Wei
Li, Lin
Zhang, Wenfu
Liu, Siyang
Li, Hanping
Liu, Yongjian
Bao, Zuoyi
Han, Jingwan
Song, Hongbin
Li, Jingyun
author_facet Chang, Shuai
Zhuang, Daomin
Guo, Wei
Li, Lin
Zhang, Wenfu
Liu, Siyang
Li, Hanping
Liu, Yongjian
Bao, Zuoyi
Han, Jingwan
Song, Hongbin
Li, Jingyun
author_sort Chang, Shuai
collection PubMed
description OBJECTIVES: This study was designed to identify common HIV-1 mutation complexes affecting the slope of inhibition curve, and to propose a new parameter incorporating both the IC50 and the slope to evaluate phenotypic resistance. METHODS: Utilizing site-directed mutagenesis, we constructed 22 HIV-1 common mutation complexes. IC50 and slope of 10 representative approved drugs and a novel agent against these mutations were measured to determine the resistance phenotypes. The values of new parameter incorporating both the IC50 and the slope of the inhibition curve were calculated, and the correlations between parameters were assessed. RESULTS: Depending on the class of drug, there were intrinsic differences in how the resistance mutations affected the drug parameters. All of the mutations resulted in large increases in the IC50s of nucleoside reverse transcriptase inhibitors. The effects of the mutations on the slope were the most apparent when examining their effects on the inhibition of non-nucleoside reverse transcriptase inhibitors and protease inhibitors. For example, some mutations, such as V82A, had no effect on IC50, but reduced the slope. We proposed a new concept, termed IIP(atoxic), on the basis of IC50, slope and the maximum limiting concentrations of the drug. The IIP(atoxic) values of 10 approved drugs and 1 novel agent were calculated, and were closely related to the IIP(max) values (r > 0.95, p < 0.001). CONCLUSIONS: This study confirms that resistance mutations cannot be accurately assessed by IC50 alone, because it tends to underestimate the degree of resistance. The slope parameter is of very importance in the measurement of drug resistance and the effect can be applied to more complex patterns of resistance. This is the most apparent when testing the effects of the mutations on protease inhibitors activity. We also propose a new index, IIP(atoxic), which incorporates both the IC50 and the slope. This new index could complement current IIP indices, thereby enabling predict the efficacy of pre-clinical drugs for which human pharmacokinetic is not available.
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spelling pubmed-47730732016-03-07 The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope Chang, Shuai Zhuang, Daomin Guo, Wei Li, Lin Zhang, Wenfu Liu, Siyang Li, Hanping Liu, Yongjian Bao, Zuoyi Han, Jingwan Song, Hongbin Li, Jingyun PLoS One Research Article OBJECTIVES: This study was designed to identify common HIV-1 mutation complexes affecting the slope of inhibition curve, and to propose a new parameter incorporating both the IC50 and the slope to evaluate phenotypic resistance. METHODS: Utilizing site-directed mutagenesis, we constructed 22 HIV-1 common mutation complexes. IC50 and slope of 10 representative approved drugs and a novel agent against these mutations were measured to determine the resistance phenotypes. The values of new parameter incorporating both the IC50 and the slope of the inhibition curve were calculated, and the correlations between parameters were assessed. RESULTS: Depending on the class of drug, there were intrinsic differences in how the resistance mutations affected the drug parameters. All of the mutations resulted in large increases in the IC50s of nucleoside reverse transcriptase inhibitors. The effects of the mutations on the slope were the most apparent when examining their effects on the inhibition of non-nucleoside reverse transcriptase inhibitors and protease inhibitors. For example, some mutations, such as V82A, had no effect on IC50, but reduced the slope. We proposed a new concept, termed IIP(atoxic), on the basis of IC50, slope and the maximum limiting concentrations of the drug. The IIP(atoxic) values of 10 approved drugs and 1 novel agent were calculated, and were closely related to the IIP(max) values (r > 0.95, p < 0.001). CONCLUSIONS: This study confirms that resistance mutations cannot be accurately assessed by IC50 alone, because it tends to underestimate the degree of resistance. The slope parameter is of very importance in the measurement of drug resistance and the effect can be applied to more complex patterns of resistance. This is the most apparent when testing the effects of the mutations on protease inhibitors activity. We also propose a new index, IIP(atoxic), which incorporates both the IC50 and the slope. This new index could complement current IIP indices, thereby enabling predict the efficacy of pre-clinical drugs for which human pharmacokinetic is not available. Public Library of Science 2016-03-01 /pmc/articles/PMC4773073/ /pubmed/26930645 http://dx.doi.org/10.1371/journal.pone.0149467 Text en © 2016 Chang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Chang, Shuai
Zhuang, Daomin
Guo, Wei
Li, Lin
Zhang, Wenfu
Liu, Siyang
Li, Hanping
Liu, Yongjian
Bao, Zuoyi
Han, Jingwan
Song, Hongbin
Li, Jingyun
The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope
title The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope
title_full The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope
title_fullStr The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope
title_full_unstemmed The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope
title_short The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope
title_sort antiviral activity of approved and novel drugs against hiv-1 mutations evaluated under the consideration of dose-response curve slope
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773073/
https://www.ncbi.nlm.nih.gov/pubmed/26930645
http://dx.doi.org/10.1371/journal.pone.0149467
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