Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras
α-Synuclein aggregation under pathological conditions is one of the causes of related neurodegenerative diseases. PROTACs (proteolysis targeting chimeras) are bifunctional small molecules that induce a post-translational erasure of proteins via the ubiquitination of target proteins by E3 ubiquitin l...
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MDPI AG
2023-05-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/11/4458 |
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| author | Tianzhi Wen Jian Chen Wenqian Zhang Jiyan Pang |
| author_facet | Tianzhi Wen Jian Chen Wenqian Zhang Jiyan Pang |
| author_sort | Tianzhi Wen |
| collection | DOAJ |
| description | α-Synuclein aggregation under pathological conditions is one of the causes of related neurodegenerative diseases. PROTACs (proteolysis targeting chimeras) are bifunctional small molecules that induce a post-translational erasure of proteins via the ubiquitination of target proteins by E3 ubiquitin ligase and subsequent proteasomal degradation. However, few research studies have been conducted for targeted protein degradation of α-synuclein aggregates. In this article, we have designed and synthesized a series of small-molecule degraders <b>1</b>–<b>9</b> based on a known α-synuclein aggregation inhibitor sery384. In silico docking studies of sery384 with α-synuclein aggregates were accomplished to ensure that the compounds bound to α-synuclein aggregates specifically. The protein level of α-synuclein aggregates was determined to evaluate the degradation efficiency of PROTAC molecules on α-synuclein aggregates in vitro. The results show that compound <b>5</b> had the most significant degradation effect, with DC<sub>50</sub> of 5.049 μM, and could induce the degradation of α-synuclein aggregates in a time- and dose-dependent manner in vitro. Furthermore, compound <b>5</b> could inhibit the elevation of the ROS level caused by overexpression and aggregation of α-synuclein and protect H293T cells from α-synuclein toxicity. Conclusively, our results provide a new class of small-molecule degraders and an experimental basis for the treatment of α-synuclein related neurodegenerative diseases. |
| first_indexed | 2024-03-11T03:01:22Z |
| format | Article |
| id | doaj.art-2295b344a34445cd84d034597b887653 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T03:01:22Z |
| publishDate | 2023-05-01 |
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| series | Molecules |
| spelling | doaj.art-2295b344a34445cd84d034597b8876532023-11-18T08:16:55ZengMDPI AGMolecules1420-30492023-05-012811445810.3390/molecules28114458Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting ChimerasTianzhi Wen0Jian Chen1Wenqian Zhang2Jiyan Pang3School of Chemistry, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Chemistry, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Chemistry, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Chemistry, Sun Yat-sen University, Guangzhou 510006, Chinaα-Synuclein aggregation under pathological conditions is one of the causes of related neurodegenerative diseases. PROTACs (proteolysis targeting chimeras) are bifunctional small molecules that induce a post-translational erasure of proteins via the ubiquitination of target proteins by E3 ubiquitin ligase and subsequent proteasomal degradation. However, few research studies have been conducted for targeted protein degradation of α-synuclein aggregates. In this article, we have designed and synthesized a series of small-molecule degraders <b>1</b>–<b>9</b> based on a known α-synuclein aggregation inhibitor sery384. In silico docking studies of sery384 with α-synuclein aggregates were accomplished to ensure that the compounds bound to α-synuclein aggregates specifically. The protein level of α-synuclein aggregates was determined to evaluate the degradation efficiency of PROTAC molecules on α-synuclein aggregates in vitro. The results show that compound <b>5</b> had the most significant degradation effect, with DC<sub>50</sub> of 5.049 μM, and could induce the degradation of α-synuclein aggregates in a time- and dose-dependent manner in vitro. Furthermore, compound <b>5</b> could inhibit the elevation of the ROS level caused by overexpression and aggregation of α-synuclein and protect H293T cells from α-synuclein toxicity. Conclusively, our results provide a new class of small-molecule degraders and an experimental basis for the treatment of α-synuclein related neurodegenerative diseases.https://www.mdpi.com/1420-3049/28/11/4458α-synucleinprotein aggregatesPROTAC (proteolysis-targeting chimera) |
| spellingShingle | Tianzhi Wen Jian Chen Wenqian Zhang Jiyan Pang Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras Molecules α-synuclein protein aggregates PROTAC (proteolysis-targeting chimera) |
| title | Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras |
| title_full | Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras |
| title_fullStr | Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras |
| title_full_unstemmed | Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras |
| title_short | Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras |
| title_sort | design synthesis and biological evaluation of α synuclein proteolysis targeting chimeras |
| topic | α-synuclein protein aggregates PROTAC (proteolysis-targeting chimera) |
| url | https://www.mdpi.com/1420-3049/28/11/4458 |
| work_keys_str_mv | AT tianzhiwen designsynthesisandbiologicalevaluationofasynucleinproteolysistargetingchimeras AT jianchen designsynthesisandbiologicalevaluationofasynucleinproteolysistargetingchimeras AT wenqianzhang designsynthesisandbiologicalevaluationofasynucleinproteolysistargetingchimeras AT jiyanpang designsynthesisandbiologicalevaluationofasynucleinproteolysistargetingchimeras |