Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors
Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain‐containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have be...
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Online Access: | http://dx.doi.org/10.1002/ange.202405860 https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.202405860 |
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crwiley:10.1002/ange.202405860 2024-06-23T07:47:01+00:00 Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors Sun, Chunxiao Jiang, Yuqi Li, Changlong Sun, Simin Lin, Jiaqi Wang, Wenxue Zhou, Luning Li, Liping Shah, Mudassir Che, Qian Zhang, Guojian Wang, De Zhu, Tianjiao Li, Dehai 2024 http://dx.doi.org/10.1002/ange.202405860 https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.202405860 en eng Wiley http://onlinelibrary.wiley.com/termsAndConditions#vor Angewandte Chemie ISSN 0044-8249 1521-3757 journal-article 2024 crwiley https://doi.org/10.1002/ange.202405860 2024-06-11T04:43:40Z Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain‐containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A−C (1−3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17‐895, which represent the first naturally occurring naphthopyrone‐macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro‐inflammatory cytokine IL‐1β release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome. Article in Journal/Newspaper Antarc* Antarctic Wiley Online Library Antarctic Angewandte Chemie |
institution |
Open Polar |
collection |
Wiley Online Library |
op_collection_id |
crwiley |
language |
English |
description |
Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain‐containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A−C (1−3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17‐895, which represent the first naturally occurring naphthopyrone‐macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro‐inflammatory cytokine IL‐1β release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome. |
format |
Article in Journal/Newspaper |
author |
Sun, Chunxiao Jiang, Yuqi Li, Changlong Sun, Simin Lin, Jiaqi Wang, Wenxue Zhou, Luning Li, Liping Shah, Mudassir Che, Qian Zhang, Guojian Wang, De Zhu, Tianjiao Li, Dehai |
spellingShingle |
Sun, Chunxiao Jiang, Yuqi Li, Changlong Sun, Simin Lin, Jiaqi Wang, Wenxue Zhou, Luning Li, Liping Shah, Mudassir Che, Qian Zhang, Guojian Wang, De Zhu, Tianjiao Li, Dehai Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors |
author_facet |
Sun, Chunxiao Jiang, Yuqi Li, Changlong Sun, Simin Lin, Jiaqi Wang, Wenxue Zhou, Luning Li, Liping Shah, Mudassir Che, Qian Zhang, Guojian Wang, De Zhu, Tianjiao Li, Dehai |
author_sort |
Sun, Chunxiao |
title |
Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors |
title_short |
Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors |
title_full |
Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors |
title_fullStr |
Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors |
title_full_unstemmed |
Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors |
title_sort |
discovery, total synthesis, and anti‐inflammatory evaluation of naturally occurring naphthopyrone‐macrolide hybrids as potent nlrp3 inflammasome inhibitors |
publisher |
Wiley |
publishDate |
2024 |
url |
http://dx.doi.org/10.1002/ange.202405860 https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.202405860 |
geographic |
Antarctic |
geographic_facet |
Antarctic |
genre |
Antarc* Antarctic |
genre_facet |
Antarc* Antarctic |
op_source |
Angewandte Chemie ISSN 0044-8249 1521-3757 |
op_rights |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
op_doi |
https://doi.org/10.1002/ange.202405860 |
container_title |
Angewandte Chemie |
_version_ |
1802650148223844352 |