Piericones A and B as Potent Antithrombotics : Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture
Extracellular protein disulfide isomerase (PDI) is a promising target for thrombotic-related diseases. Four potent PDI inhibitors with unprecedented chemical architectures, piericones A-D (1-4), were isolated from Pieris japonica. Their structures were elucidated by spectroscopic data analysis, chemical methods, quantum 13C nuclear magnetic resonance DP4+ and electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Piericones A (1) and B (2) were nanomolar noncompetitive PDI inhibitors possessing an unprecedented 3,6,10,15-tetraoxatetracyclo[7.6.0.04,9.01,12]pentadecane motif with nine contiguous stereogenic centers. Their biosynthetic pathways were proposed to include a key intermolecular aldol reaction and an intramolecular 1,2-migration reaction. Piericone A (1) significantly inhibited in vitro platelet aggregation and fibrin formation and in vivo thrombus formation via the inhibition of extracellular PDI without increasing the bleeding risk. The molecular docking and dynamics simulation of 1 and 2 provided a novel structure basis to develop PDI inhibitors as potent antithrombotics.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:145 |
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| Enthalten in: |
Journal of the American Chemical Society - 145(2023), 5 vom: 08. Feb., Seite 3196-3203 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zheng, Guijuan [VerfasserIn] |
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| Links: |
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| Themen: |
EC 5.3.4.1 |
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| Anmerkungen: |
Date Completed 09.02.2023 Date Revised 27.02.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/jacs.2c12963 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Extracellular protein disulfide isomerase (PDI) is a promising target for thrombotic-related diseases. Four potent PDI inhibitors with unprecedented chemical architectures, piericones A-D (1-4), were isolated from Pieris japonica. Their structures were elucidated by spectroscopic data analysis, chemical methods, quantum 13C nuclear magnetic resonance DP4+ and electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Piericones A (1) and B (2) were nanomolar noncompetitive PDI inhibitors possessing an unprecedented 3,6,10,15-tetraoxatetracyclo[7.6.0.04,9.01,12]pentadecane motif with nine contiguous stereogenic centers. Their biosynthetic pathways were proposed to include a key intermolecular aldol reaction and an intramolecular 1,2-migration reaction. Piericone A (1) significantly inhibited in vitro platelet aggregation and fibrin formation and in vivo thrombus formation via the inhibition of extracellular PDI without increasing the bleeding risk. The molecular docking and dynamics simulation of 1 and 2 provided a novel structure basis to develop PDI inhibitors as potent antithrombotics | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Protein Disulfide-Isomerases |2 NLM | |
| 650 | 7 | |a EC 5.3.4.1 |2 NLM | |
| 650 | 7 | |a Fibrinolytic Agents |2 NLM | |
| 700 | 1 | |a Lv, Keyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Lang |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Yuanyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Biao |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yenan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yaofeng |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jiangeng |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Pengfei |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Xulin |e verfasserin |4 aut | |
| 700 | 1 | |a Horgen, F David |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Guangmin |e verfasserin |4 aut | |
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