Thiophene‐Based Dual Modulators of Aβ and Tau Aggregation

Abstract

Alzheimer's disease is characterized by the accumulation of amyloid beta (Aβ) and Tau aggregates in the brain, which induces various pathological events resulting in neurodegeneration. There have been continuous efforts to develop modulators of the Aβ and Tau aggregation process to halt or modify disease progression. A few small-molecule-based inhibitors that target both Aβ and Tau pathology have been reported. Here, we report the screening of a targeted library of small molecules to modulate Aβ and Tau aggregation together with their in vitro, in silico and cellular studies. In vitro ThT fluorescence assay, dot blot assay, gel electrophoresis and transmission electron microscopy (TEM) results have shown that thiophenebased lead molecules effectively modulate Aβ aggregation and inhibit Tau aggregation. In silico studies performed by employing molecular docking, molecular dynamics and binding-free energy calculations have helped in understanding the mechanism of interaction of the lead thiophene compounds with Aβ and Tau fibril targets. In cellulo studies revealed that the lead candidate is biocompatible and effectively ameliorates neuronal cells from Aβ and Tau-mediated amyloid toxicity.

Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

“…Recently, we have screened a focused library of 52 thiophene-based small molecules targeting Aβ aggregation and identified five lead candidates. 180 The detailed ThT assay, dot blot assay, gel electrophoresis and transmission electron microscopy (TEM) results demonstrated compound 8 as a good modulator of Aβ and tau aggregation. Compound 8 is non-toxic up to 100 μM and rescues neuronal cells from both Aβ and tau toxicity.…”

“…We have screened a focussed library of thiophene-based small molecules and identified compound 8 with anti-aggregation activity and rescue SH-SY5Y cells from tau toxicity. 180 Eisenberg and co-workers have designed structure-based peptides of unnatural amino acids and identified an all D-peptide (D-TLKIVW) inhibitor of tau aggregation (Fig. 8B).…”

“…We have screened a focussed library of thiophene-based small molecules and identified compound 8 with anti-aggregation activity and rescued SH-SY5Y cells from tau toxicity. 180 …”

Tau-targeting therapy in Alzheimer’s disease: critical advances and future opportunities

“…In addition to inhibiting tau aggregation, there are still some inhibitors reported to act as dual inhibitors of Aβ and tau. Curcumin can effectively disaggregate Aβ as well as preventing fibril and oligomer formation at low concentration [121] . At the same time, some small molecules (e.g., thiophene and ortho catechol) that have not yet entered clinical research are also playing the same role [122,123] .…”

Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation

“…There have been efforts to develop dual modulators targeting two etiologies to alleviate AD pathology. We reported the design and evaluation of small molecules and peptidomimetic modulators targeting Aβ/tau and autophagy. − Other groups have reported small molecules targeting dual pathological factors. − Our group and others have reported a number of small molecules, hybrid modulators, tripeptide analogues, peptidomimetics, and natural products with multifunctional ability to target Aβ aggregation inhibition, metal–Aβ toxicity, ROS, oxidative stress, mitochondrial damage, and AChE. − …”