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Synthesis and evaluation of esterified Hsp70 agonists in cellular models of protein aggregation and folding

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.

Publication metadata

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


DOI: 10.1016/j.bmc.2018.11.011


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