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Lookup NU author(s): Professor Tiago OuteiroORCiD
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© 2018 Elsevier Ltd Over-expression of the Hsp70 molecular chaperone prevents protein aggregation and ameliorates neurodegenerative disease phenotypes in model systems. We identified an Hsp70 activator, MAL1-271, that reduces α-synuclein aggregation in a Parkinson's Disease model. We now report that MAL1-271 directly increases the ATPase activity of a eukaryotic Hsp70. Next, twelve MAL1-271 derivatives were synthesized and examined in a refined α-synuclein aggregation model as well as in an assay that monitors maturation of a disease-causing Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutant, which is also linked to Hsp70 function. Compared to the control, MAL1-271 significantly increased the number of cells lacking α-synuclein inclusions and increased the steady-state levels of the CFTR mutant. We also found that a nitrile-containing MAL1-271 analog exhibited similar effects in both assays. None of the derivatives exhibited cellular toxicity at concentrations up to 100 μm, nor were cellular stress response pathways induced. These data serve as a gateway for the continued development of a new class of Hsp70 agonists with efficacy in these and potentially other disease models.
Author(s): Chiang AN, Liang M, Dominguez-Meijide A, Masaracchia C, Goeckeler-Fried JL, Mazzone CS, Newhouse DW, Kendsersky NM, Yates ME, Manos-Turvey A, Needham PG, Outeiro TF, Wipf P, Brodsky JL
Publication type: Article
Publication status: Published
Journal: Bioorganic and Medicinal Chemistry
Year: 2019
Volume: 27
Issue: 1
Pages: 79-91
Print publication date: 01/01/2019
Online publication date: 15/11/2018
Acceptance date: 09/11/2018
ISSN (print): 0968-0896
ISSN (electronic): 1464-3391
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/j.bmc.2018.11.011
DOI: 10.1016/j.bmc.2018.11.011
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