Ball, Sarah R;
Adamson, Julius SP;
Sullivan, Michael A;
Zimmermann, Manuela R;
Lo, Victor;
Sanz-Hernandez, Maximo;
Jiang, Xiaofan;
... Sunde, Margaret; + view all
(2022)
Perphenazine-Macrocycle Conjugates Rapidly Sequester the Aβ42 Monomer and Prevent Formation of Toxic Oligomers and Amyloid.
ACS Chemical Neuroscience
, 14
(1)
pp. 87-98.
10.1021/acschemneuro.2c00498.
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Abstract
Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the disease outcome is to use small molecules to limit the conversion of monomeric amyloid (Aβ42) to cytotoxic amyloid oligomers and fibrils. We have synthesized modulators of amyloid assembly that are unlike others studied to date: these compounds act primarily by sequestering the Aβ42 monomer. We provide kinetic and nuclear magnetic resonance data showing that these perphenazine conjugates divert the Aβ42 monomer into amorphous aggregates that are not cytotoxic. Rapid monomer sequestration by the compounds reduces fibril assembly, even in the presence of pre-formed fibrillar seeds. The compounds are therefore also able to disrupt monomer-dependent secondary nucleation, the autocatalytic process that generates the majority of toxic oligomers. The inhibitors have a modular design that is easily varied, aiding future exploration and use of these tools to probe the impact of distinct Aβ42 species populated during amyloid assembly.
| Type: | Article |
|---|---|
| Title: | Perphenazine-Macrocycle Conjugates Rapidly Sequester the Aβ42 Monomer and Prevent Formation of Toxic Oligomers and Amyloid |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acschemneuro.2c00498 |
| Publisher version: | https://doi.org/10.1021/acschemneuro.2c00498 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Alzheimer’s disease, amyloid, inhibition, kinetic analysis, monomer sequestration, oligomers |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10162859 |
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