Structure Dependent Differential Modulation of Aβ Fibrillization by Selenadiazole-Based Inhibitors

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.