Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5
The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020
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| Online Access: | https://hdl.handle.net/1721.1/124926 |
| _version_ | 1826212731447934976 |
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| author | Chan, Yasmin Li, Fu-Shuang Levsh, Olesya Weng, Jing-Ke |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Chan, Yasmin Li, Fu-Shuang Levsh, Olesya Weng, Jing-Ke |
| author_sort | Chan, Yasmin |
| collection | MIT |
| description | The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop novel icariin PDE5 inhibitors with improved potency and specificity. We synthesized six novel semi-synthetic icariin analogs as well as three naturally occurring icariin analogs, and characterized the structure-activity relationship in the context of human PDE5 inhibition using in vitro enzyme inhibition and kinetics assays and molecular modeling. Mammalian-cell-based assays and in vitro enzyme inhibition assays against human PDE6C further helped to identify the most potent and selective icariin analogs. Our results reveal the synergistic contribution of functional groups at the C3 and C7 positions of the icariin backbone towards PDE5 inhibition. Whereas a hydrophobic and flexible alkanol group at the C7 position is sufficient to enhance icariin analog potency, combining this group with a hydrophilic sugar group at the C3 position leads to further enhancement of potency and promotes specificity towards PDE5 versus PDE6C. In particular, compounds 3 and 7 exhibit Ki values of 0.036 ± 0.005 μM and 0.036 ± 0.007 μM towards PDE5 respectively, which are approaching those of commercial PDE5 inhibitors, and can effectively reduce GMP levels in cultured human BJ-hTERT cells. This study identifies novel icariin analogs as potent and selective PDE5 inhibitors poised to become lead compounds for further pharmaceutical development. |
| first_indexed | 2024-09-23T15:36:32Z |
| format | Article |
| id | mit-1721.1/124926 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:36:32Z |
| publishDate | 2020 |
| publisher | Public Library of Science (PLoS) |
| record_format | dspace |
| spelling | mit-1721.1/1249262022-09-29T15:02:03Z Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5 Chan, Yasmin Li, Fu-Shuang Levsh, Olesya Weng, Jing-Ke Whitehead Institute for Biomedical Research Massachusetts Institute of Technology. Department of Biology General Biochemistry, Genetics and Molecular Biology General Agricultural and Biological Sciences General Medicine The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop novel icariin PDE5 inhibitors with improved potency and specificity. We synthesized six novel semi-synthetic icariin analogs as well as three naturally occurring icariin analogs, and characterized the structure-activity relationship in the context of human PDE5 inhibition using in vitro enzyme inhibition and kinetics assays and molecular modeling. Mammalian-cell-based assays and in vitro enzyme inhibition assays against human PDE6C further helped to identify the most potent and selective icariin analogs. Our results reveal the synergistic contribution of functional groups at the C3 and C7 positions of the icariin backbone towards PDE5 inhibition. Whereas a hydrophobic and flexible alkanol group at the C7 position is sufficient to enhance icariin analog potency, combining this group with a hydrophilic sugar group at the C3 position leads to further enhancement of potency and promotes specificity towards PDE5 versus PDE6C. In particular, compounds 3 and 7 exhibit Ki values of 0.036 ± 0.005 μM and 0.036 ± 0.007 μM towards PDE5 respectively, which are approaching those of commercial PDE5 inhibitors, and can effectively reduce GMP levels in cultured human BJ-hTERT cells. This study identifies novel icariin analogs as potent and selective PDE5 inhibitors poised to become lead compounds for further pharmaceutical development. Pew Scholars Program in the Biomedical Sciences (Grant 27345) Searle Scholars Program (Grant 15-SSP-162) 2020-04-29T16:45:49Z 2020-04-29T16:45:49Z 2019-09-20 2020-02-03T17:58:41Z Article http://purl.org/eprint/type/JournalArticle 1932-6203 https://hdl.handle.net/1721.1/124926 Chan, Yasmin et al. “Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.” PLoS ONE 14 (2019): e0222803 © 2019 The Author(s) en 10.1371/journal.pone.0222803 PLoS ONE Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science (PLoS) PLoS |
| spellingShingle | General Biochemistry, Genetics and Molecular Biology General Agricultural and Biological Sciences General Medicine Chan, Yasmin Li, Fu-Shuang Levsh, Olesya Weng, Jing-Ke Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5 |
| title | Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5 |
| title_full | Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5 |
| title_fullStr | Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5 |
| title_full_unstemmed | Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5 |
| title_short | Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5 |
| title_sort | exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase 5 |
| topic | General Biochemistry, Genetics and Molecular Biology General Agricultural and Biological Sciences General Medicine |
| url | https://hdl.handle.net/1721.1/124926 |
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