De novo design of a mechano-pharmaceutical screening platform against formation of individual beta-amyloid oligomers.

IF 7.9 2区 综合性期刊 Q1 CHEMISTRY, MULTIDISCIPLINARY
Shankar Pandey, Mathias Bogetoft Danielsen, Yuan Xiang, Zhilei Zhang, Grinsun Sharma, Byeong Tak Jeon, Shixi Song, Yitong Hao, Gunan Zhang, Niels Johan Christensen, Kasper Kildegaard Sørensen, Pernille Harris, Pravin Pokhrel, Richard Cunningham, Min-Ho Kim, Yongsheng Leng, Chenguang Lou, Hanbin Mao
{"title":"<i>De novo</i> design of a mechano-pharmaceutical screening platform against formation of individual beta-amyloid oligomers.","authors":"Shankar Pandey, Mathias Bogetoft Danielsen, Yuan Xiang, Zhilei Zhang, Grinsun Sharma, Byeong Tak Jeon, Shixi Song, Yitong Hao, Gunan Zhang, Niels Johan Christensen, Kasper Kildegaard Sørensen, Pernille Harris, Pravin Pokhrel, Richard Cunningham, Min-Ho Kim, Yongsheng Leng, Chenguang Lou, Hanbin Mao","doi":"10.1016/j.xcrp.2024.102336","DOIUrl":null,"url":null,"abstract":"<p><p>Small molecules that can reduce the neurotoxic beta-amyloid (Aβ) aggregates in the brain provide a potential treatment for Alzheimer disease (AD). Most screening methods for small-molecule hits focus on the overall Aβ aggregations without a specific target, such as the very first association step (i.e., nucleation) <i>en route</i> to the Aβ oligomers. Located in the middle of a full-length Aβ peptide, Aβ<sub>19-20</sub> (diphenylalanine or FF) nucleates the neurotoxic Aβ oligomer formation. Here, we innovate a single-molecule screen method in optical tweezers by targeting the nucleation process in Aβ aggregation, namely FF-dimerization. With a 121-compound National Institutes of Health (NIH) library, we identify 12 inhibitors and 8 stimulants that can inhibit/promote Aβ<sub>19-20</sub> dimerization significantly. The representative hits are subjected to the thioflavin T and cell toxicity assays to confirm their inhibiting or stimulating activities. By replacing FF with longer Aβ sequences, our single-molecule platform may identify more specific and potent small molecules to fight AD.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"5 12","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905928/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Physical Science","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1016/j.xcrp.2024.102336","RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

Abstract

Small molecules that can reduce the neurotoxic beta-amyloid (Aβ) aggregates in the brain provide a potential treatment for Alzheimer disease (AD). Most screening methods for small-molecule hits focus on the overall Aβ aggregations without a specific target, such as the very first association step (i.e., nucleation) en route to the Aβ oligomers. Located in the middle of a full-length Aβ peptide, Aβ19-20 (diphenylalanine or FF) nucleates the neurotoxic Aβ oligomer formation. Here, we innovate a single-molecule screen method in optical tweezers by targeting the nucleation process in Aβ aggregation, namely FF-dimerization. With a 121-compound National Institutes of Health (NIH) library, we identify 12 inhibitors and 8 stimulants that can inhibit/promote Aβ19-20 dimerization significantly. The representative hits are subjected to the thioflavin T and cell toxicity assays to confirm their inhibiting or stimulating activities. By replacing FF with longer Aβ sequences, our single-molecule platform may identify more specific and potent small molecules to fight AD.

从头设计抗单个β-淀粉样蛋白寡聚体形成的机械药物筛选平台。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cell Reports Physical Science
Cell Reports Physical Science Energy-Energy (all)
CiteScore
11.40
自引率
2.20%
发文量
388
审稿时长
62 days
期刊介绍: Cell Reports Physical Science, a premium open-access journal from Cell Press, features high-quality, cutting-edge research spanning the physical sciences. It serves as an open forum fostering collaboration among physical scientists while championing open science principles. Published works must signify significant advancements in fundamental insight or technological applications within fields such as chemistry, physics, materials science, energy science, engineering, and related interdisciplinary studies. In addition to longer articles, the journal considers impactful short-form reports and short reviews covering recent literature in emerging fields. Continually adapting to the evolving open science landscape, the journal reviews its policies to align with community consensus and best practices.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信