Dementia and other neurological conditions, most significantly Alzheimer’s, represent a class of neurodegenerative diseases connected to the accumulation of the Tau protein in the human brain. These conditions embody one of the principal causes of death and disability in elderly individuals, with no effective therapy being discovered or developed as of yet.

An international team of scientists led by Dr. Gergely Tóth at University of Cambridge (UK) and at Hungarian Academy of Sciences (Hungary), with Professor Eckhard Mandelkow at Deutsches Zentrum fu-r Neurodegenerative Erkrankungen (Germany) in collaboration with Novalix (France) and Elan Pharmaceuticals (USA) reported the development of a novel therapeutic approach to target the monomeric Tau protein by small molecule drug candidates to maintain the protein’s native function and reduce its misfolding and aggregation, which is linked to the onset of these diseases. The study was recently published in Current Alzheimer’s Research and was selected as Editor’s Choice by Prof. D. K. Lahiri’s, (Editor-in-Chief,)

The Tau protein is an intrinsically disordered protein (IDP), a class of proteins that lack stable 3D structure. Because of this, targeting it using small molecules has been challenging. To tackle this challenge, the scientific team applied a unique binding screening methodology, applied by Novalix, to detect the binding between small molecules and Tau. This led to the identification of a diverse set of novel fragment and lead-like small molecules capable of binding Tau, a part of which reduced the aggregation of Tau in vitro and in a cellular model of Tauopathies.

The study demonstrated for the first time that monomeric Tau can be a viable receptor of small drug-like molecules, and supports the potential and practical feasibility of the therapeutic strategy to target early phases of the aggregation pathway of Tau and potentially other IDPs by small molecules, thereby eliminating the formation of potential toxic misfolded protein species. The researchers suggest that the presented drug discovery paradigm has general applicability, “the drug discovery approach that we present can be applied to other IDPs linked to other misfolding diseases such as Alzheimer’s and Parkinson’s diseases”.

Marcus Pickhardt, Thomas Neumann, Daniel Schwizer, Kari Callaway, Michele Vendruscolo, Dale Schenk, Peter St. George-Hyslop, Eva M. Mandelkow, Christopher M. Dobson, Lisa McConlogue, Eckhard Mandelkow and Gergely Toth.

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