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Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants
Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcription and block the replication of HIV‐1. Currently, NNRTIs are usually used as part of a three‐drug combination given to patients as antiretroviral therapy. These combinations involve other classes of anti‐HIV‐1 drugs,...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821153/ https://www.ncbi.nlm.nih.gov/pubmed/32743937 http://dx.doi.org/10.1111/cbdd.13766 |
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author | Smith, Steven J. Pauly, Gary T. Hewlett, Katharine Schneider, Joel P. Hughes, Stephen H. |
author_facet | Smith, Steven J. Pauly, Gary T. Hewlett, Katharine Schneider, Joel P. Hughes, Stephen H. |
author_sort | Smith, Steven J. |
collection | PubMed |
description | Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcription and block the replication of HIV‐1. Currently, NNRTIs are usually used as part of a three‐drug combination given to patients as antiretroviral therapy. These combinations involve other classes of anti‐HIV‐1 drugs, commonly nucleoside reverse transcriptase inhibitors (NRTIs). However, attempts are being made to develop two‐drug maintenance therapies, some of which involve an NNRTI and an integrase strand transfer inhibitor. This has led to a renewed interest in developing novel NNRTIs, with a major emphasis on designing compounds that can effectively inhibit the known NNRTI‐resistant mutants. We have generated and tested novel rilpivirine (RPV) analogs. The new compounds were designed to exploit a small opening in the upper right periphery of the NNRTI‐binding pocket. The best of the new compounds, 12, was a more potent inhibitor of the NNRTI‐resistant mutants we tested than either doravirine or efavirenz but was inferior to RPV. We describe the limitations on the modifications that can be appended to the “upper right side” of the RPV core and the effects of substituting other cores for the central pyrimidine core of RPV and make suggestions about how this information can be used in NNRTI design. |
format | Online Article Text |
id | pubmed-7821153 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78211532021-01-26 Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants Smith, Steven J. Pauly, Gary T. Hewlett, Katharine Schneider, Joel P. Hughes, Stephen H. Chem Biol Drug Des Research Articles Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcription and block the replication of HIV‐1. Currently, NNRTIs are usually used as part of a three‐drug combination given to patients as antiretroviral therapy. These combinations involve other classes of anti‐HIV‐1 drugs, commonly nucleoside reverse transcriptase inhibitors (NRTIs). However, attempts are being made to develop two‐drug maintenance therapies, some of which involve an NNRTI and an integrase strand transfer inhibitor. This has led to a renewed interest in developing novel NNRTIs, with a major emphasis on designing compounds that can effectively inhibit the known NNRTI‐resistant mutants. We have generated and tested novel rilpivirine (RPV) analogs. The new compounds were designed to exploit a small opening in the upper right periphery of the NNRTI‐binding pocket. The best of the new compounds, 12, was a more potent inhibitor of the NNRTI‐resistant mutants we tested than either doravirine or efavirenz but was inferior to RPV. We describe the limitations on the modifications that can be appended to the “upper right side” of the RPV core and the effects of substituting other cores for the central pyrimidine core of RPV and make suggestions about how this information can be used in NNRTI design. John Wiley and Sons Inc. 2020-09-17 2021-01 /pmc/articles/PMC7821153/ /pubmed/32743937 http://dx.doi.org/10.1111/cbdd.13766 Text en © 2020 The Authors. Chemical Biology & Drug Design published by John Wiley & Sons A/S. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Smith, Steven J. Pauly, Gary T. Hewlett, Katharine Schneider, Joel P. Hughes, Stephen H. Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants |
title | Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants |
title_full | Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants |
title_fullStr | Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants |
title_full_unstemmed | Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants |
title_short | Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants |
title_sort | structure‐based non‐nucleoside inhibitor design: developing inhibitors that are effective against resistant mutants |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821153/ https://www.ncbi.nlm.nih.gov/pubmed/32743937 http://dx.doi.org/10.1111/cbdd.13766 |
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