Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues
AbstractPrions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2191164 |
| _version_ | 1797400993266139136 |
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| author | Dong Hwan Kim Jaehyeon Kim Hakmin Lee Dongyun Lee So Myoung Im Ye Eun Kim Miryeong Yoo Yong-Pil Cheon Jason C. Bartz Young-Jin Son Eun-Kyoung Choi Yong-Sun Kim Jae-Ho Jeon Hyo Shin Kim Sungeun Lee Chongsuk Ryou Tae-gyu Nam |
| author_facet | Dong Hwan Kim Jaehyeon Kim Hakmin Lee Dongyun Lee So Myoung Im Ye Eun Kim Miryeong Yoo Yong-Pil Cheon Jason C. Bartz Young-Jin Son Eun-Kyoung Choi Yong-Sun Kim Jae-Ho Jeon Hyo Shin Kim Sungeun Lee Chongsuk Ryou Tae-gyu Nam |
| author_sort | Dong Hwan Kim |
| collection | DOAJ |
| description | AbstractPrions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrPSc but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC50 = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC50 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrPSc in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics. |
| first_indexed | 2024-03-09T02:02:29Z |
| format | Article |
| id | doaj.art-1fe3e8bdff3a416d802cf6eccfe45604 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-03-09T02:02:29Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-1fe3e8bdff3a416d802cf6eccfe456042023-12-08T03:24:20ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138110.1080/14756366.2023.2191164Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analoguesDong Hwan Kim0Jaehyeon Kim1Hakmin Lee2Dongyun Lee3So Myoung Im4Ye Eun Kim5Miryeong Yoo6Yong-Pil Cheon7Jason C. Bartz8Young-Jin Son9Eun-Kyoung Choi10Yong-Sun Kim11Jae-Ho Jeon12Hyo Shin Kim13Sungeun Lee14Chongsuk Ryou15Tae-gyu Nam16Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDivision of Developmental Biology and Physiology, Department of Biotechnology, Sungshin University, Seoul, KoreaDepartment of Medical Microbiology and Immunology, School of Medicine, Creighton University, Omaha, NE, USADepartment of Pharmacy, Sunchon National University, Suncheon, Republic of KoreaIlsong Institute of Life Science, Hallym University, Seoul, Republic of KoreaIlsong Institute of Life Science, Hallym University, Seoul, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of KoreaAbstractPrions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrPSc but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC50 = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC50 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrPSc in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.https://www.tandfonline.com/doi/10.1080/14756366.2023.2191164Prion disease Creutzfeldt–Jakob diseaseprion aggregation formation assayacylthiosemicarbazide |
| spellingShingle | Dong Hwan Kim Jaehyeon Kim Hakmin Lee Dongyun Lee So Myoung Im Ye Eun Kim Miryeong Yoo Yong-Pil Cheon Jason C. Bartz Young-Jin Son Eun-Kyoung Choi Yong-Sun Kim Jae-Ho Jeon Hyo Shin Kim Sungeun Lee Chongsuk Ryou Tae-gyu Nam Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues Journal of Enzyme Inhibition and Medicinal Chemistry Prion disease Creutzfeldt–Jakob disease prion aggregation formation assay acylthiosemicarbazide |
| title | Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues |
| title_full | Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues |
| title_fullStr | Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues |
| title_full_unstemmed | Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues |
| title_short | Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues |
| title_sort | synthesis and anti prion aggregation activity of acylthiosemicarbazide analogues |
| topic | Prion disease Creutzfeldt–Jakob disease prion aggregation formation assay acylthiosemicarbazide |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2191164 |
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