Jeff Y. L. Lam, Timothy S. Chisholm, Hadia Almahli, Elizabeth A. English, Zengjie Xia, Yunzhao Wu, Matthew R. Cheetham, Christopher A. Hunter and David Klenerman
{"title":"单分子阵列检测α -突触核蛋白小分子聚集体","authors":"Jeff Y. L. Lam, Timothy S. Chisholm, Hadia Almahli, Elizabeth A. English, Zengjie Xia, Yunzhao Wu, Matthew R. Cheetham, Christopher A. Hunter and David Klenerman","doi":"10.1039/D4SC07649D","DOIUrl":null,"url":null,"abstract":"<p >Protein aggregates are promising biomarkers for early diagnosis of neurodegenerative disorders. Single-Molecule Array (SiMoA) is a powerful method to detect these aggregates at ultra-low concentrations in biofluids. Herein, we report a next-generation SiMoA assay using chemically synthesized small molecules, rather than antibodies, to capture alpha-synuclein aggregates, a protein hallmark in Parkinson's Disease and other synucleinopathies. These small molecule-based capturing agents contain aggregate-binding head groups, and a backbone functionalized with a primary amine for bead conjugation in the SiMoA assay. The most promising molecule, <strong>BF-79-2</strong>, captured recombinant alpha-synuclein aggregates, specifically excluding monomers, at picomolar concentrations. <strong>BF-79-2</strong> also captured alpha-synuclein aggregates in human blood. Replacing antibodies with small molecules as capturing agents on the SiMoA platform enhances the assay versatility, since small molecules can be screened <em>in silico</em> and synthesized without laborious molecular biology techniques. The application of small molecules as capturing agents broadens the capabilities of the SiMoA platform, rendering it more adaptable for biomarker discovery and disease diagnostics.</p>","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":" 29","pages":" 13435-13448"},"PeriodicalIF":7.4000,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2025/sc/d4sc07649d?page=search","citationCount":"0","resultStr":"{\"title\":\"Detecting alpha-synuclein aggregates with small molecules on single-molecule array†\",\"authors\":\"Jeff Y. L. Lam, Timothy S. Chisholm, Hadia Almahli, Elizabeth A. English, Zengjie Xia, Yunzhao Wu, Matthew R. Cheetham, Christopher A. Hunter and David Klenerman\",\"doi\":\"10.1039/D4SC07649D\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Protein aggregates are promising biomarkers for early diagnosis of neurodegenerative disorders. Single-Molecule Array (SiMoA) is a powerful method to detect these aggregates at ultra-low concentrations in biofluids. Herein, we report a next-generation SiMoA assay using chemically synthesized small molecules, rather than antibodies, to capture alpha-synuclein aggregates, a protein hallmark in Parkinson's Disease and other synucleinopathies. These small molecule-based capturing agents contain aggregate-binding head groups, and a backbone functionalized with a primary amine for bead conjugation in the SiMoA assay. The most promising molecule, <strong>BF-79-2</strong>, captured recombinant alpha-synuclein aggregates, specifically excluding monomers, at picomolar concentrations. <strong>BF-79-2</strong> also captured alpha-synuclein aggregates in human blood. Replacing antibodies with small molecules as capturing agents on the SiMoA platform enhances the assay versatility, since small molecules can be screened <em>in silico</em> and synthesized without laborious molecular biology techniques. The application of small molecules as capturing agents broadens the capabilities of the SiMoA platform, rendering it more adaptable for biomarker discovery and disease diagnostics.</p>\",\"PeriodicalId\":9909,\"journal\":{\"name\":\"Chemical Science\",\"volume\":\" 29\",\"pages\":\" 13435-13448\"},\"PeriodicalIF\":7.4000,\"publicationDate\":\"2025-06-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.rsc.org/en/content/articlepdf/2025/sc/d4sc07649d?page=search\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemical Science\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2025/sc/d4sc07649d\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Science","FirstCategoryId":"92","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2025/sc/d4sc07649d","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Detecting alpha-synuclein aggregates with small molecules on single-molecule array†
Protein aggregates are promising biomarkers for early diagnosis of neurodegenerative disorders. Single-Molecule Array (SiMoA) is a powerful method to detect these aggregates at ultra-low concentrations in biofluids. Herein, we report a next-generation SiMoA assay using chemically synthesized small molecules, rather than antibodies, to capture alpha-synuclein aggregates, a protein hallmark in Parkinson's Disease and other synucleinopathies. These small molecule-based capturing agents contain aggregate-binding head groups, and a backbone functionalized with a primary amine for bead conjugation in the SiMoA assay. The most promising molecule, BF-79-2, captured recombinant alpha-synuclein aggregates, specifically excluding monomers, at picomolar concentrations. BF-79-2 also captured alpha-synuclein aggregates in human blood. Replacing antibodies with small molecules as capturing agents on the SiMoA platform enhances the assay versatility, since small molecules can be screened in silico and synthesized without laborious molecular biology techniques. The application of small molecules as capturing agents broadens the capabilities of the SiMoA platform, rendering it more adaptable for biomarker discovery and disease diagnostics.
期刊介绍:
Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.