Discovery and Development of Cyclic Peptide Proteasome Stimulators
The proteasome degrades proteins, which is essential for cellular homeostasis. Ubiquitin independent proteolysis degrades highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation of misfolded prot...
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| Veröffentlicht in: | Chembiochem : a European journal of chemical biology 2024-02, Vol.25 (3), p.e202300671-n/a |
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| creator | Nelson, Samantha Harris, Timothy J. Muli, Christine S. Maresh, Marianne E. Baker, Braden Smith, Chloe Neumann, Chris Trader, Darci J. Parkinson, Elizabeth I. |
| description | The proteasome degrades proteins, which is essential for cellular homeostasis. Ubiquitin independent proteolysis degrades highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation of misfolded proteins. In this work, cyclic peptide proteasome stimulators (CyPPSs) that enhance the clearance of misfolded proteins were discovered. In the initial screen of predicted natural products (pNPs), several cyclic peptides were found to stimulate the 20S core particle (20S CP). Development of a robust structural activity relationship led to the identification of potent, cell permeable CyPPSs. In vitro assays revealed that CyPPSs stimulate degradation of highly disordered and misfolded proteins without affecting ordered proteins. Furthermore, using a novel flow‐based assay for proteasome activity, several CyPPSs were found to stimulate the 20S CP in cellulo. Overall, this work describes the development of CyPPSs as chemical tools capable of stimulating the proteasome and provides strong support for proteasome stimulation as a therapeutic strategy for neurodegenerative diseases.
Cyclic peptide proteasome stimulators: Cyclic peptides inspired by natural products activate ubiquitin independent degradation of disordered proteins. Development and utilization of a flow‐based proteasome assay enabled confirmation of the activity of cyclic peptides in cells, making them valuable chemical tools for studying proteasome activation. |
| doi_str_mv | 10.1002/cbic.202300671 |
| format | Article |
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Cyclic peptide proteasome stimulators: Cyclic peptides inspired by natural products activate ubiquitin independent degradation of disordered proteins. Development and utilization of a flow‐based proteasome assay enabled confirmation of the activity of cyclic peptides in cells, making them valuable chemical tools for studying proteasome activation.</description><subject>Biodegradation</subject><subject>Core particles</subject><subject>Degradation</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>macrocycles</subject><subject>Natural products</subject><subject>Neurodegenerative diseases</subject><subject>Neurodegenerative Diseases - drug therapy</subject><subject>Peptides</subject><subject>Peptides, Cyclic - metabolism</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>proteasome</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Proteasomes</subject><subject>Protein folding</subject><subject>Proteins</subject><subject>Proteins - metabolism</subject><subject>Proteolysis</subject><subject>stimulation</subject><subject>Stimulators</subject><subject>Ubiquitin</subject><issn>1439-4227</issn><issn>1439-7633</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNqFkUtP3DAURq0KVCjttssqEptuZvArTryqOqEFJCSQyt7y4xqMknhqJ4Pm3zejmQ6PDStb8rnH99OH0FeC5wRjemZNsHOKKcNYVOQDOiacyVklGDvY3Tml1RH6lPMjxlgKRj6iI1bjsiSyOkaL85BtXEFaF7p3xTmsoI3LDvqhiL5o1rYNtriF5RAcFLcpDqBz7KD4M4RubPUQU_6MDr1uM3zZnSfo7vevu-Zydn1zcdX8vJ7ZkjIycyVAxY2nYKQ2tbNWGOaMx9gQWgshuOGidqX3VBBvSC1MXUkPjjtaWspO0I-tdjmaDpydVky6VcsUOp3WKuqgXr_04UHdx5UiWErGCJsM33eGFP-OkAfVTeGhbXUPccyK1rKWJed889npG_Qxjqmf4ikqKZacMI4nar6lbIo5J_D7bQhWm3rUph61r2ca-PYywx7_38cEyC3wFFpYv6NTzeKqeZb_Ay4UnSY</recordid><startdate>20240201</startdate><enddate>20240201</enddate><creator>Nelson, Samantha</creator><creator>Harris, Timothy J.</creator><creator>Muli, Christine S.</creator><creator>Maresh, Marianne E.</creator><creator>Baker, Braden</creator><creator>Smith, Chloe</creator><creator>Neumann, Chris</creator><creator>Trader, Darci J.</creator><creator>Parkinson, Elizabeth I.</creator><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3665-5522</orcidid><orcidid>https://orcid.org/0000-0003-2850-7105</orcidid></search><sort><creationdate>20240201</creationdate><title>Discovery and Development of Cyclic Peptide Proteasome Stimulators</title><author>Nelson, Samantha ; 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Ubiquitin independent proteolysis degrades highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation of misfolded proteins. In this work, cyclic peptide proteasome stimulators (CyPPSs) that enhance the clearance of misfolded proteins were discovered. In the initial screen of predicted natural products (pNPs), several cyclic peptides were found to stimulate the 20S core particle (20S CP). Development of a robust structural activity relationship led to the identification of potent, cell permeable CyPPSs. In vitro assays revealed that CyPPSs stimulate degradation of highly disordered and misfolded proteins without affecting ordered proteins. Furthermore, using a novel flow‐based assay for proteasome activity, several CyPPSs were found to stimulate the 20S CP in cellulo. Overall, this work describes the development of CyPPSs as chemical tools capable of stimulating the proteasome and provides strong support for proteasome stimulation as a therapeutic strategy for neurodegenerative diseases.
Cyclic peptide proteasome stimulators: Cyclic peptides inspired by natural products activate ubiquitin independent degradation of disordered proteins. Development and utilization of a flow‐based proteasome assay enabled confirmation of the activity of cyclic peptides in cells, making them valuable chemical tools for studying proteasome activation.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>38055197</pmid><doi>10.1002/cbic.202300671</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-3665-5522</orcidid><orcidid>https://orcid.org/0000-0003-2850-7105</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Chembiochem : a European journal of chemical biology, 2024-02, Vol.25 (3), p.e202300671-n/a |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Biodegradation Core particles Degradation Homeostasis Humans macrocycles Natural products Neurodegenerative diseases Neurodegenerative Diseases - drug therapy Peptides Peptides, Cyclic - metabolism Peptides, Cyclic - pharmacology proteasome Proteasome Endopeptidase Complex - metabolism Proteasomes Protein folding Proteins Proteins - metabolism Proteolysis stimulation Stimulators Ubiquitin |
| title | Discovery and Development of Cyclic Peptide Proteasome Stimulators |
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