期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 1, 页码 79-91出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.11.011
关键词
Molecular chaperone; Proteostasis; Parkinson's Disease; Cystic Fibrosis; alpha-Synuclein; CFTR
资金
- National Institutes of Health [GM075061, DK079307]
- Cystic Fibrosis Foundation Therapeutics [BRODSK13XX0, BRODSK18G0]
- Galician Government (Programa de axuda a etapa posdoutoral, XUGA, GAIN) [ED481B 2017/053]
- DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)
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 alpha-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 alpha-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 alpha-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 mu m, 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.
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