Tau protein in the brain can become overly phosphorylated, and the resulting clumped proteins form solid aggregates that are disruptive to cell and tissue function. Clearing out this phosphorylated protein is one of the strategies under development for the treatment of Alzheimer's disease - without noteworthy clinical success so far, but recall that it took something like twenty years and innumerable clinical trials to produce a working approach to amyloid-β clearance. Many different therapeutic approaches to targeting specifically phosphorylated tau are presently at some stage of development, and here find a review of the current landscape.
Hyperphosphorylation of tau initiates the intracellular formation of neurofibrillary tangles, a hallmark of a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Pick's disease, multiple system atrophy, etc. Intracellular accumulation of hyperphosphorylated tau (pTau) decreases microtubule stability, induces protein aggregation, and impairs neuronal plasticity. Therefore, downregulation or removal of hyperphosphorylated tau (pTau) holds promise for the therapy of these diseases.
However, there remains a great challenge in the development of pTau-targeted drugs. For example, direct application of either tau kinase inhibitors or phosphatase activators may induce unacceptable toxic side effects, because the majority of these enzymes concurrently modulate numerous signaling pathways other than tau. Another way to eliminate pTau is immunotherapy, which employs tau-targeted antibodies to specifically facilitate tau degradation. Although these antibody drugs have shown moderate efficacy for alleviating cognitive impairment in AD patients, they are usually high-cost and it is generally difficult for antibodies to penetrate into the cells to bind tau.
A new kind of hetero-bifunctional molecule, namely targeting chimera, has attracted increasing attention in drug discovery in recent years for its ability to recognize and change the property of a certain protein of interest (POI), typically by enhancing the proximity between the POI and a specific effector, such as ubiquitin ligases for proteolysis targeting chimeras (PROTACs), and autophagosome protein LC3 for autophagy-tethering compounds (ATTECs). Several pTau targeting TACs have been developed in recent years, including dephosphorylation-targeting chimeras (DEPTACs), proteolysis targeting chimeras (PROTACs) for pTau, phosphorylation targeting chimeras (phosTACs), and affinity-directed phosphatase (AdPhosphatases) system.
In this review, we briefly introduce tau and its role in neurodegenerative diseases, provide progress in the development of pTau targeting therapies, and discuss their advantages and limitations.
Link: https://doi.org/10.1016/j.medp.2024.100060
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