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Alzheimer's disease (AD) is a severe, growing, multifactorial disorder affecting millions of people worldwide characterized by cognitive decline and neurodegeneration. The accumulation of tau protein into paired helical filaments is one of the major pathological hallmarks of AD and has gained the interest of researchers as a potential drug target to treat AD. Lately, Artificial Intelligence (AI) has revolutionized the drug discovery process by speeding it up and reducing the overall cost. As a part of our continuous effort to identify potential tau aggregation inhibitors, and leveraging the power of AI, in this study, we used a fully automated AI-assisted ligand-based virtual screening tool, PyRMD to screen a library of 12 million compounds from the ZINC database to identify potential tau aggregation inhibitors. The preliminary hits from virtual screening were filtered for similar compounds and pan-assay interference compounds (the compounds containing reactive functional groups which can interfere with the assays) using RDKit. Further, the selected compounds were prioritized based on their molecular docking score with the binding pocket of tau where the binding pockets were identified using replica exchange molecular dynamics simulation. Thirty-three compounds showing good docking scores for all the tau clusters were selected and were further subjected to in silico pharmacokinetic prediction. Finally, top 10 compounds were selected for molecular dynamics simulation and MMPBSA binding free energy calculations resulting in the identification of UNK_175, UNK_1027, UNK_1172, UNK_1173, UNK_1237, UNK_1518, and UNK_2181 as potential tau aggregation inhibitors. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that mainly affects older adults. One of the pathological hallmarks of AD is abnormally aggregated Tau protein that forms fibrillar deposits in the brain. In AD, Tau pathology correlates strongly with clinical symptoms, cognitive dysfunction, and neuronal death. Methods: We aimed to develop novel therapeutic D-amino acid peptides as Tau fibrillization inhibitors. It has been previously demonstrated that D-amino acid peptides are protease stable and less immunogenic than L-peptides, and these characteristics may render them suitable for in vivo applications. Using a phage display procedure against wild type full-length Tau (TauFL), we selected a novel Tau binding L-peptide and synthesized its D-amino acid version ISAD1 and its retro inversed form, ISAD1rev, respectively. Results: While ISAD1rev inhibited Tau aggregation only moderately, ISAD1 bound to Tau in the aggregation-prone PHF6 region and inhibited fibrillization of TauFL, disease-associated mutant full-length Tau (TauFLΔK, TauFL-A152T, TauFL-P301L), and pro-aggregant repeat domain Tau mutant (TauRDΔK). ISAD1 and ISAD1rev induced the formation of large high molecular weight TauFL and TauRDΔK oligomers that lack proper Thioflavin-positive β-sheet conformation even at lower concentrations. In silico modeling of ISAD1 Tau interaction at the PHF6 site revealed a binding mode similar to those known for other PHF6 binding peptides. Cell culture experiments demonstrated that ISAD1 and its inverse form are taken up by N2a-TauRDΔK cells efficiently and prevent cytotoxicity of externally added Tau fibrils as well as of internally expressed TauRDΔK. Conclusions: ISAD1 and related peptides may be suitable for therapy development of AD by promoting off-pathway assembly of Tau, thus preventing its toxicity. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by severe motor, cognitive and psychiatric impairments. While motor deficits often confirm diagnosis, cognitive dysfunctions usually manifest early in the disease process and are consistently ranked among the leading factors that impact the patients' quality of life. The genetic component of HD, a mutation in the huntingtin (HTT) gene, is traditionally presented as the main contributor to disease pathology. However, accumulating evidence suggests the implication of the microtubule-associated tau protein to the pathogenesis and therefore, proposes an alternative conceptual framework where tau and mutant huntingtin (mHTT) act conjointly to drive neurodegeneration and cognitive dysfunction. This perspective on disease etiology offers new avenues to design therapeutic interventions and could leverage decades of research on Alzheimer's disease (AD) and other tauopathies to rapidly advance drug discovery. In this mini review, we examine the breadth of tau-targeting treatments currently tested in the preclinical and clinical settings for AD and other tauopathies, and discuss the potential application of these strategies to HD. [ABSTRACT FROM AUTHOR]

Tau plays an important pathological role in a group of neurodegenerative diseases called tauopathies, including Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration. In each disease, tau self-assembles abnormally to form filaments that deposit in the brain. Tau is a natively unfolded protein that can adopt distinct structures in different pathological disorders. Cryo-electron microscopy has recently provided a series of structures for the core of the filaments purified from brain tissue from patients with different tauopathies and revealed that they share a common core region, while differing in their specific conformation. This structurally resolvable part of the core is contained within a proteolytically stable core region from the repeat domain initially isolated from AD tau filaments. Tau has recently become an important target for therapy. Recent work has suggested that the prevention of tau self-assembly may be effective in slowing the progression of Alzheimer's disease and other tauopathies. Here we review the work that explores the importance of tau filament structures and tau self-assembly mechanisms, as well as examining model systems that permit the exploration of the mode of action of potential inhibitors. [ABSTRACT FROM AUTHOR]

Small molecular weight compounds able to inhibit formation of tau oligomers and fibrils have already been tested for Alzheimer’s disease (AD) treatment. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (also known as methylene blue) was investigated in a 24-week Phase II study in 321 mild-to-moderate AD patients at the doses of 69, 138, and 228 mg/day. This trial failed to show significant positive effects of MT in the overall patient population. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected patients and cerebral blood flow in mildly affected patients. A follow-up compound (TRx0237) claimed to be more bioavailable and less toxic than MT, is now being developed. Phase III clinical trials on this novel TAI in AD and in the behavioral variant of frontotemporal dementia are underway. [ABSTRACT FROM PUBLISHER]