Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes
<b>PF74</b> and <b>11L</b>, as potent modulators of the HIV-1 capsid protein, have been demonstrated to act at both early and late stages in the HIV-1 life cycle. However, their clearance is high in human liver microsomes (HLMs). The main goal of this study was to clarify the...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/12/8/752 |
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| author | Shujing Xu Lin Sun Dang Ding Xujie Zhang Xinyong Liu Peng Zhan |
| author_facet | Shujing Xu Lin Sun Dang Ding Xujie Zhang Xinyong Liu Peng Zhan |
| author_sort | Shujing Xu |
| collection | DOAJ |
| description | <b>PF74</b> and <b>11L</b>, as potent modulators of the HIV-1 capsid protein, have been demonstrated to act at both early and late stages in the HIV-1 life cycle. However, their clearance is high in human liver microsomes (HLMs). The main goal of this study was to clarify the metabolism of <b>PF74</b> and <b>11L</b> in HLMs, and provide guidance for future structural optimization. To accomplish this, the phase-I metabolites of <b>PF74</b> and <b>11L</b>, resulting from in vitro incubation with HLMs, were investigated via ultra-performance liquid chromatography–ultraviolet–high-resolution mass spectrometry (UPLC–UV–HRMS). The results show that 17 phase-I metabolites were putatively annotated for <b>PF74</b>, whereas 16 phase-I metabolites were found for <b>11L</b>. The main metabolic pathways of <b>PF74</b> in HLMs were oxidation and demethylation, and the secondary metabolic pathway was hydrolysis; thus, the di-oxidation and demethylation products (<b>M7</b>, <b>M9</b>, <b>M11</b>, and <b>M14</b>) were found to be major metabolites of <b>PF74</b> in HLMs. In comparison, the main metabolic pathways of <b>11L</b> in HLMs were oxidation, demethylation, dehydrogenation, and oxidative deamination, with <b>M6′</b>, <b>M11′</b>, <b>M15′</b>, and <b>M16′</b> as the main metabolites. We suggest that the indole ring and <i>N</i>-methyl group of <b>PF74</b>, and the aniline group, benzene ring R1′, <i>N</i>-methyl, and methoxy group of <b>11L</b>, were the main metabolic soft spots. Therefore, our research illuminates structural optimization options in seeking improved HIV-1 CA modulators. |
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| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-09T09:52:11Z |
| publishDate | 2022-08-01 |
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| series | Metabolites |
| spelling | doaj.art-b74f85ae1f714c21babfb74925a69ea32023-12-02T00:00:34ZengMDPI AGMetabolites2218-19892022-08-0112875210.3390/metabo12080752Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver MicrosomesShujing Xu0Lin Sun1Dang Ding2Xujie Zhang3Xinyong Liu4Peng Zhan5Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China<b>PF74</b> and <b>11L</b>, as potent modulators of the HIV-1 capsid protein, have been demonstrated to act at both early and late stages in the HIV-1 life cycle. However, their clearance is high in human liver microsomes (HLMs). The main goal of this study was to clarify the metabolism of <b>PF74</b> and <b>11L</b> in HLMs, and provide guidance for future structural optimization. To accomplish this, the phase-I metabolites of <b>PF74</b> and <b>11L</b>, resulting from in vitro incubation with HLMs, were investigated via ultra-performance liquid chromatography–ultraviolet–high-resolution mass spectrometry (UPLC–UV–HRMS). The results show that 17 phase-I metabolites were putatively annotated for <b>PF74</b>, whereas 16 phase-I metabolites were found for <b>11L</b>. The main metabolic pathways of <b>PF74</b> in HLMs were oxidation and demethylation, and the secondary metabolic pathway was hydrolysis; thus, the di-oxidation and demethylation products (<b>M7</b>, <b>M9</b>, <b>M11</b>, and <b>M14</b>) were found to be major metabolites of <b>PF74</b> in HLMs. In comparison, the main metabolic pathways of <b>11L</b> in HLMs were oxidation, demethylation, dehydrogenation, and oxidative deamination, with <b>M6′</b>, <b>M11′</b>, <b>M15′</b>, and <b>M16′</b> as the main metabolites. We suggest that the indole ring and <i>N</i>-methyl group of <b>PF74</b>, and the aniline group, benzene ring R1′, <i>N</i>-methyl, and methoxy group of <b>11L</b>, were the main metabolic soft spots. Therefore, our research illuminates structural optimization options in seeking improved HIV-1 CA modulators.https://www.mdpi.com/2218-1989/12/8/752PF7411Lcapsid modulatorshuman liver microsomesUPLC–UV–HRMSmetabolite identification |
| spellingShingle | Shujing Xu Lin Sun Dang Ding Xujie Zhang Xinyong Liu Peng Zhan Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes Metabolites PF74 11L capsid modulators human liver microsomes UPLC–UV–HRMS metabolite identification |
| title | Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes |
| title_full | Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes |
| title_fullStr | Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes |
| title_full_unstemmed | Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes |
| title_short | Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes |
| title_sort | metabolite identification of hiv 1 capsid modulators pf74 and 11l in human liver microsomes |
| topic | PF74 11L capsid modulators human liver microsomes UPLC–UV–HRMS metabolite identification |
| url | https://www.mdpi.com/2218-1989/12/8/752 |
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