Alzheimer's disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The worldwide effort to develop peptide-based inhibitors of amyloid-β (Aβ) aggregation can be considered an unplanned combinatorial experiment. An understanding of what has been done and achieved may advance our understanding of AD pathology and the discovery of effective therapeutic agents. We review here the history of such peptide-based inhibitors, including those based on the Aβ sequence and those not derived from that sequence, containing both natural and unnatural amino acid building blocks. Peptide-based aggregation inhibitors hold significant promise for future AD therapy owing to their high selectivity, effectiveness, low toxicity, good tolerance, low accumulation in tissues, high chemical and biological diversity, possibility of rational design, and highly developed methods for analyzing their mode of action, proteolytic stability (modified peptides), and blood-brain barrier (BBB) permeability.

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Amyloid beta (Aβ) peptide aggregation is considered as one of the key hallmarks of Alzheimer’s disease (AD). Moreover, Aβ peptide aggregation increases considerably in the presence of metal ions and triggers the generation of reactive oxygen species (ROS), which ultimately leads to oxidative stress and neuronal damage. Based on the ‘multitarget-directed ligands’ (MTDLs) strategy, we designed, synthesized, and evaluated a novel series of triazole-based compounds for AD treatment via experimental and computational methods. Among the designed MTDLs [4­(a–x)], the triazole derivative 4v exhibited the most potent inhibition of self-induced Aβ42 aggregation (78.02%) with an IC50 value of 4.578 ± 0.109 μM and also disassembled the preformed Aβ42 aggregates significantly. In addition, compound 4v showed excellent metal chelating ability and maintained copper in the redox-dormant state to prevent the generation of ROS in copper-ascorbate redox cycling. Further, 4v significantly inhibited Cu2+-induced Aβ42 aggregation and disassembled the Cu2+-induced Aβ42 protofibrils as compared to the reference compound clioquinol (CQ). Importantly, 4v did not show cytotoxicity and was able to inhibit the toxicity induced by Aβ42 aggregates in SH-SY5Y cells. Molecular docking results confirmed the strong binding of 4v with Aβ42 monomer and Aβ42 protofibril structure. The experimental and molecular docking results highlighted that 4v is a promising multifunctional lead compound for AD.

CuO nanowires exhibited highest catalytic efficiency for the cycloaddition reaction between azide and terminal alkyne, featuring short reaction time, soft reaction conditions and complete regioselectivity.

Amyloid-β (Aβ) aggregation plays a key role in the pathogenesis of Alzheimer’s disease (AD). Along with this, the presence of redox-active metals like Cu2+ further enhances Aβ aggregation, oxidative stress, and cellular toxicity. In this study, we have rationally designed, synthesized, and evaluated a series of triazole–peptide conjugates as potential promiscuous ligands capable of targeting different pathological factors of AD. In particular, peptidomimetic DS2 showed the best inhibitory activity against Aβ aggregation with an IC50 value of 2.43 ± 0.05 μM. In addition, DS2 disaggregates preformed Aβ42 fibrils, chelates metal ions, inhibits metal-mediated Aβ aggregation, significantly controls reactive oxygen species production, and reduces oxidative stress. DS2 exhibited very low cytotoxicity and significantly ameliorated the Aβ-induced toxicity in differentiated neuroblastoma cells, SH-SY5Y. In addition, alteration in the fibrillary architecture of Aβ42 in the absence and presence of DS2 was validated by transmission electron microscopy (TEM) images. To shed light on the inhibitory mechanism of DS2 against Aβ aggregation and disassembly of the protofibril structure, molecular dynamics (MD) simulations have been performed. DS2 binds preferentially with the central hydrophobic core (CHC) residues of Aβ42 monomer and chains D–E of Aβ42 protofibril. The dictionary of secondary structure of proteins analysis indicated a noteworthy increase in the helix content from 38.5 to 61% and, notably, a complete loss of β-sheet content of Aβ42 monomer when DS2 is added to it. DS2 suppressed Aβ42 monomer aggregation by preserving helical conformations and was able to reduce the production of aggregation-prone β-sheet structures, which are consistent with ThT, circular dichroism, and TEM assay that indicate a reduction in the formation of toxic Aβ42 aggregated species on the addition of DS2. Moreover, DS2 destabilized the Aβ42 protofibril structure by significantly reducing the binding affinity between chains D–E of protofibril, which highlighted the disruption of interchain interactions and subsequent deformation of the protofibril structure. The results of the present study demonstrate that triazole–peptide conjugates may be valuable chemotypes for the development of promising multifunctional AD therapeutic candidates.