Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants
With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or po...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/14178 |
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| author | Ling Ma Jiajia Wen Biao Dong Jinming Zhou Shangjiu Hu Juxian Wang Yucheng Wang Mei Zhu Shan Cen |
| author_facet | Ling Ma Jiajia Wen Biao Dong Jinming Zhou Shangjiu Hu Juxian Wang Yucheng Wang Mei Zhu Shan Cen |
| author_sort | Ling Ma |
| collection | DOAJ |
| description | With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2′ ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors <b>15d</b> and <b>15f</b> exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors. |
| first_indexed | 2024-03-09T18:16:55Z |
| format | Article |
| id | doaj.art-af68b91dc4e8436dae09fe076d8aa626 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:16:55Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-af68b91dc4e8436dae09fe076d8aa6262023-11-24T08:39:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221417810.3390/ijms232214178Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 VariantsLing Ma0Jiajia Wen1Biao Dong2Jinming Zhou3Shangjiu Hu4Juxian Wang5Yucheng Wang6Mei Zhu7Shan Cen8Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, ChinaKey Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua 321004, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, ChinaWith the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2′ ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors <b>15d</b> and <b>15f</b> exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors.https://www.mdpi.com/1422-0067/23/22/14178HIV-1 protease inhibitorsphenolpolyphenolenzymatic inhibitory activityantiviral activitydarunavir-resistant HIV-1 variant |
| spellingShingle | Ling Ma Jiajia Wen Biao Dong Jinming Zhou Shangjiu Hu Juxian Wang Yucheng Wang Mei Zhu Shan Cen Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants International Journal of Molecular Sciences HIV-1 protease inhibitors phenol polyphenol enzymatic inhibitory activity antiviral activity darunavir-resistant HIV-1 variant |
| title | Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants |
| title_full | Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants |
| title_fullStr | Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants |
| title_full_unstemmed | Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants |
| title_short | Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants |
| title_sort | design and evaluation of novel hiv 1 protease inhibitors containing phenols or polyphenols as p2 ligands with high activity against drv resistant hiv 1 variants |
| topic | HIV-1 protease inhibitors phenol polyphenol enzymatic inhibitory activity antiviral activity darunavir-resistant HIV-1 variant |
| url | https://www.mdpi.com/1422-0067/23/22/14178 |
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