biostudies-literaturePandey SNCI NIH HHS102336https://www.ebi.ac.uk/biostudies/studies/S-EPMC11905928biostudies-literatureUnknown5(12)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_19-20 (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 Aβ_19-20 dimCell reports. Physical science&lt;i&gt;De novo&lt;/i&gt; design of a mechano-pharmaceutical screening platform against formation of individual beta-amyloid oligomers.PMC11905928R01 CA252827Zhang GPokhrel PHarris PSharma GMao HHao YJeon BTPandey SChristensen NJZhang ZDanielsen MBLou CLeng YXiang YSong SSorensen KKKim MHCunningham Rfalse&lt;i&gt;De novo&lt;/i&gt; design of a mechano-pharmaceutical screening platform against formation of individual beta-amyloid oligomers.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_19-20 (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 Aβ_19-20 dim2024-01-01T00:00:00Z2024 Dec2025-04-26T03:23:41.458Z2025-04-06T10:51:16.939ZS-EPMC119059284008358410.1016/j.xcrp.2024.102336