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

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 1; pp. 79 - 91
• Main Authors: Chiang, Annette N., Liang, Mary, Dominguez-Meijide, Antonio, Masaracchia, Caterina, Goeckeler-Fried, Jennifer L., Mazzone, Carly S., Newhouse, David W., Kendsersky, Nathan M., Yates, Megan E., Manos-Turvey, Alexandra, Needham, Patrick G., Outeiro, Tiago F., Wipf, Peter, Brodsky, Jeffrey L.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2019; Elsevier
• Subjects: Adenosine Triphosphatases - metabolism; alpha-Synuclein - agonists; alpha-Synuclein - metabolism; Biochemistry & Molecular Biology; Cell Line, Tumor; CFTR; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Enzyme Activators - chemical synthesis; Enzyme Activators - chemistry; Enzyme Activators - pharmacology; Enzyme Activators - toxicity; Esters - chemical synthesis; Esters - chemistry; Esters - pharmacology; Esters - toxicity; HEK293 Cells; HSP70 Heat-Shock Proteins - agonists; HSP70 Heat-Shock Proteins - metabolism; Humans; Life Sciences & Biomedicine; Molecular chaperone; Molecular Structure; Parkinson’s Disease; Pharmacology & Pharmacy; Physical Sciences; Protein Folding - drug effects; Protein Multimerization - drug effects; Proteostasis; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Pyrimidinones - toxicity; Saccharomyces cerevisiae - enzymology; Science & Technology; Structure-Activity Relationship; α-Synuclein; α-Synuclein; Parkinson’s Disease; Proteostasis; Cystic Fibrosis; Molecular chaperone; CFTR; DELTA-F508-CFTR; BINDING-SPECIFICITY; HSP90; DOMAIN; ATPASE; Parkinson's Disease; TRANSMEMBRANE CONDUCTANCE REGULATOR; HEAT-SHOCK PROTEINS; MOLECULAR CHAPERONE FUNCTION; SSA1; alpha-Synuclein
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.11.011

[Display omitted] 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.