De novo 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<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.
Authors
- Gunan Zhang (ORCID: https://orcid.org/0000-0001-9875-8917)
- Pravin Pokhrel (ORCID: https://orcid.org/0000-0003-4259-6087)
- Shixi Song (ORCID: https://orcid.org/0000-0002-1795-3719)
- Yongsheng Leng (ORCID: https://orcid.org/0000-0002-3558-5016)
- Byeong Tak Jeon
- Shankar Pandey (ORCID: https://orcid.org/0000-0001-5576-6714)
- Chenguang Lou (ORCID: https://orcid.org/0000-0002-9521-8285)
- N. J. Christensen (ORCID: https://orcid.org/0000-0001-9588-2656)
- Grinsun Sharma (ORCID: https://orcid.org/0000-0002-6846-7120)
- Yi Hao (ORCID: https://orcid.org/0000-0002-0248-8279)
- Richard Cunningham (ORCID: https://orcid.org/0000-0002-6081-2153)
- Hanbin Mao (ORCID: https://orcid.org/0000-0002-6720-9429)
- Mathias Bogetoft Danielsen (ORCID: https://orcid.org/0000-0001-9862-3967)
- Pernille Harris (ORCID: https://orcid.org/0000-0002-6806-4903)
- Yuan Xiang (ORCID: https://orcid.org/0000-0002-4665-3360)
- Min‐Ho Kim (ORCID: https://orcid.org/0000-0003-4834-2563)
- Zhilei Zhang (ORCID: https://orcid.org/0000-0002-6264-4333)
- Kasper K. Sørensen
Institutions
- University of Copenhagen (DK)
- Kent State University (US)
- University of Southern Denmark (DK)
- George Washington University (US)
- Chengdu University of Technology (CN)
- Science Oxford (GB)
Publication Details
- Journal
- Cell Reports Physical Science
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.xcrp.2024.102336
- Citations
- 1
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.33
Funders
- Villum Fonden
- Kent State University
- Lundbeckfonden
- Danmarks Tekniske Universitet
- H. Lundbeck A/S
- National Institutes of Health