CPD-23-46-Ubaldo Armato

To access the article, please visit: http://www.eurekaselect.com/154081

Press Release for EurekAlert! Inhibition of tau protein aggregation by rhodanine-based compounds

This research article by Dr. Eckhard Mandelkow et al has been published in Current Alzheimer Research, Volume 14, Issue 7, 2017


The design of tailored peptide-polymer conjugates as drug-specific formulation additives offers access to next generation precision additives that can render problematic small organic drugs water-soluble and improve bioavailability. The method can be applied to a large spectrum of entities of fluorescent or non-fluorescent drugs. Herein we report the solubilization of two poorly water-soluble, potential anti-Alzheimer disease (AD) drugs based on the rhodanine core. The compounds showed inhibitory activity to prevent the aggregation of Tau proteins into paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), both of which are associated with AD pathogenesis.

Using a fluorescence microscopy-based screening procedure, peptide sequences with high drug binding capacity are identified from large peptide libraries. The synthesis of corresponding peptide-poly(ethylene glycol) (peptide-PEG) conjugates leads to precision formulation additives for the potential anti-AD drugs. Whereas the PEG-blocks of the conjugates provide water solubility and drug shielding, the drug specific hosting is dominated by the peptide-segments, binding the drug in a non-covalent manner and thus bypassing the requirements of additional drug approval procedures.

Application in several bioassays of inhibition of Tau protein aggregation indicated that the formulation additives do not reduce drug efficacy and activity. The drug formulations showed a reduction of the fibril formation of the tested Tau construct comparable to the drug alone dissolved in DMSO. Thus, drug release from the conjugates is feasible. The activities of the compound-complexes in in vitro experiments on Tau4RDΔK280-expressing N2a cells were significantly enhanced, resulting in improved cell viability and reduced apoptosis, which correlates with a lower ratio of insoluble to soluble Tau aggregates.

The precision formulation additives offer opportunities for early stage drug structure or lead compound testing in DMSO free systems. This is important as DMSO is currently believed to affect relevant protein functions and might influence cell studies.

For more information, please visit http://www.eurekaselect.com/149699/article

EurekAlert! – Drug discovery paradigm targets Tau protein aggregation linked to the Alzheimer’s disease

New research demonstrates novel drug discovery paradigm to target the aggregation of the Tau protein linked to the onset of Alzheimer’s and other related neurodegenerative diseases

Dementia and other tauopathies, most notably Alzheimer’s disease, embody a class of neurodegenerative diseases associated with the aggregation of the Tau protein in the human brain. These diseases represent one of the leading causes of death and disability in the elderly population in the western world, with no current effective therapy.

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 Alzheimers Research (CAR) (2015, 12, p814-828; http://www.eurekaselect.com/135879) and was selected as Editor’s Choice by;

Prof. D. K. Lahiri


Read more here: http://www.eurekalert.org/pub_releases/2016-02/bsp-ddp022616.php 

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