image: Conventional small-molecule drugs for reducing pTau include phosphatase activators of PP2A, and kinase inhibitors of GSK3β, CDK5, etc., as well as active or passive immunotherapies targeting pTau. Following DEPTAC, a series of heterobifunctional targeting chimeras (TAC) for pTau including pTau-PROTAC, PhosTAC and AdPhosphatase system have been developed. These TACs can reduce pTau and hold potential for the treatment of tauopathies.
Credit: ©Science China Press
Hyperphosphorylation of microtubule-associated protein tau is a major driver in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer’s disease (AD) and other tauopathies. Intracellular accumulation of hyperphosphorylated tau (pTau) decreases microtubule stability, induces protein aggregation and impairs neuronal plasticity. Increasing attention has been devoted to the development of targeted therapies for modulating tau phosphorylation, including conventional protein kinase inhibitors, phosphatase activators, immunotherapies, as well as a new collection of tau-targeted hetero-bifunctional chimeras such as dephosphorylation-targeting chimeras (DEPTACs), proteolysis targeting chimeras (PROTACs) for pTau, phosphorylation targeting chimeras (phosTACs), and affinity-directed phosphatase (Adphosphatase) system. In this review, they give a brief introduction to tau and its role in neurodegenerative diseases. Mainly, they provide progress in the development of pTau targeting therapies and discuss their advantages and limitations.
https://doi.org/10.1016/j.medp.2024.100060
Journal
Medicine Plus