Synthesis and evaluation of esterified Hsp70 agonists in cellular models of protein aggregation and folding
| Autor: | Carly S. Mazzone, Antonio Dominguez-Meijide, Jeffrey L. Brodsky, Mary Liang, Tiago F. Outeiro, Annette N. Chiang, David Newhouse, Peter Wipf, Nathan M. Kendsersky, Megan E. Yates, Patrick G. Needham, Caterina Masaracchia, Alexandra Manos-Turvey, Jennifer L. Goeckeler-Fried |
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| Rok vydání: | 2019 |
| Předmět: |
Protein Folding
Clinical Biochemistry Mutant Cystic Fibrosis Transmembrane Conductance Regulator Enzyme Activators Pharmaceutical Science Pyrimidinones Saccharomyces cerevisiae Protein aggregation 01 natural sciences Biochemistry Article Structure-Activity Relationship Cell Line Tumor Cellular stress response Drug Discovery Humans HSP70 Heat-Shock Proteins Molecular Biology Adenosine Triphosphatases Molecular Structure biology 010405 organic chemistry Activator (genetics) Chemistry Organic Chemistry HEK 293 cells Esters Cystic fibrosis transmembrane conductance regulator 3. Good health 0104 chemical sciences Hsp70 Cell biology 010404 medicinal & biomolecular chemistry HEK293 Cells Proteostasis alpha-Synuclein biology.protein Molecular Medicine Protein Multimerization |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:79-91 |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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