| Autor: |
Kalsoom U; Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan., Alazmi M; Department of Information and Computer Science, College of Computer Science and Engineering, University of Ha'il, P.O. Box 2440, Ha'il 81411, Saudi Arabia., Farrukh HSUB; Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan., Chung KHK; Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia., Alshammari N; Department of Biology, College of Sciences, University of Ha'il, P.O. Box 2440, Ha'il 81411, Saudi Arabia., Kakinen A; Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia., Chotana GA; Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan., Javed I; Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia., Davis TP; Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia., Saleem RSZ; Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan. |
| Abstrakt: |
Misfolding and fibrillar aggregation of Aβ is a characteristic hallmark of Alzheimer's disease and primarily participates in neurodegenerative pathologies. There has been no breakthrough made in the therapeutic regime of Alzheimer's disease while the pharmacological interventions against Aβ are designed to sequester and clear Aβ burden from the neurological tissues. Based on the physiological relevance of Aβ, therapeutic approaches are required to inhibit and stabilize Aβ fibrillization, instead of cleaning it from the neurological system. In this context, we have designed a selenadiazole-based library of compounds against the fibrillization paradigm of Aβ. Compounds that completely inhibited the Aβ fibrillization appeared to stabilize Aβ at the monomeric stage as indicated by ThT assay, CD spectrophotometry, and TEM imaging. Partial inhibitors elongated the nucleation phase and allowed limited fibrillization of Aβ into smaller fragments with slightly higher β-sheets contents, while noninhibitors did not interfere in Aβ aggregation and resulted in mature fibrils with fibrillization kinetics similar to Aβ control. Molecular docking revealed the different binding positions of the compounds for three classes. Complete inhibitors alleviated Aβ toxicity to SH-SY5Y neuroblastoma cells and permeated across the blood-brain barrier in zebrafish larvae. The amino acid residues from Aβ peptide that interacted with the compounds from all three classes were overlapping and majorly lying in the amyloidogenic regions. However, compounds that stabilize Aβ monomers displayed higher association constants ( K a ) and lower dissociation constants ( K d ) in comparison to partial and noninhibitors, as corroborated by ITC. These results support further structure activity-based preclinical development of these selenadiazole compounds for potential anti-Alzheimer's therapy. |
