Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine
Protein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic event...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/11/9621 |
| _version_ | 1797597359383773184 |
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| author | Rosanna Maccari Rosaria Ottanà |
| author_facet | Rosanna Maccari Rosaria Ottanà |
| author_sort | Rosanna Maccari |
| collection | DOAJ |
| description | Protein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic events, thus providing a useful tool for the discovery of novel therapeutic agents. The search for allosteric PTP1B inhibitors can represent a successful strategy to identify drug-like candidates by offering the opportunity to overcome some issues related to catalytic site-directed inhibitors, which have so far hampered the development of drugs targeting this enzyme. In this context, trodusquemine (MSI-1436), a natural aminosterol that acts as a non-competitive PTP1B inhibitor, appears to be a milestone. Initially discovered as a broad-spectrum antimicrobial agent, trodusquemine exhibited a variety of unexpected properties, ranging from antidiabetic and anti-obesity activities to effects useful to counteract cancer and neurodegeneration, which prompted its evaluation in several preclinical and clinical studies. In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure–activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors. |
| first_indexed | 2024-03-11T03:05:07Z |
| format | Article |
| id | doaj.art-e4c2e6dd2b9942a1891389050284025b |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:05:07Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e4c2e6dd2b9942a1891389050284025b2023-11-18T08:01:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-012411962110.3390/ijms24119621Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from TrodusquemineRosanna Maccari0Rosaria Ottanà1Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, ItalyProtein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic events, thus providing a useful tool for the discovery of novel therapeutic agents. The search for allosteric PTP1B inhibitors can represent a successful strategy to identify drug-like candidates by offering the opportunity to overcome some issues related to catalytic site-directed inhibitors, which have so far hampered the development of drugs targeting this enzyme. In this context, trodusquemine (MSI-1436), a natural aminosterol that acts as a non-competitive PTP1B inhibitor, appears to be a milestone. Initially discovered as a broad-spectrum antimicrobial agent, trodusquemine exhibited a variety of unexpected properties, ranging from antidiabetic and anti-obesity activities to effects useful to counteract cancer and neurodegeneration, which prompted its evaluation in several preclinical and clinical studies. In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure–activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors.https://www.mdpi.com/1422-0067/24/11/9621protein tyrosine phosphatase 1Ballosteric inhibitiontrodusquemineMSI-1436diabetesobesity |
| spellingShingle | Rosanna Maccari Rosaria Ottanà Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine International Journal of Molecular Sciences protein tyrosine phosphatase 1B allosteric inhibition trodusquemine MSI-1436 diabetes obesity |
| title | Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine |
| title_full | Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine |
| title_fullStr | Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine |
| title_full_unstemmed | Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine |
| title_short | Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine |
| title_sort | can allostery be a key strategy for targeting ptp1b in drug discovery a lesson from trodusquemine |
| topic | protein tyrosine phosphatase 1B allosteric inhibition trodusquemine MSI-1436 diabetes obesity |
| url | https://www.mdpi.com/1422-0067/24/11/9621 |
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