pyrimidinones and Protein-Aggregation--Pathological

Protein misfolding and inclusion body formations are common events in neurodegenerative diseases characterized by deposition of misfolded proteins inside or outside of neurons, and are commonly referred to as "protein misfolding neurodegenerative diseases" (PMNDs). These phenotypically diverse but biochemically similar aggregates suggest a highly conserved molecular mechanism of pathogenesis. These challenges are magnified by presence of mutations that render individual proteins subject to misfolding and/or aggregation. Cell proteostasis network and molecular chaperoning are maintaining cell proteome to preserve the protein folding, refolding, oligomerization, or disaggregation, and play formidable tasks to maintain the health of organism in the face of developmental changes, environmental insults, and rigors of aging. Maintenance of cell proteome requires the orchestration of major pathways of the cellular proteostasis network (heat shock response (HSR) in the cytosol and the unfolded protein response (UPR) in the endoplasmic reticulum). Proteostasis responses culminate in transcriptional and post-transcriptional programs that up-regulate the homeostatic mechanisms. Proteostasis is strongly influenced by the general properties of individual proteins for folding, misfolding, and aggregation. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We first try to introduce some new chemical approaches to prevent the misfolding or aggregation of specific proteins via direct binding interactions. We then start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organ proteostasis. © 2016 BioFactors, 43(6):737-759, 2017.

Topics: Amyloidogenic Proteins; Animals; Chalcones; Endoplasmic Reticulum; Gene Expression Regulation; Heat-Shock Response; Humans; Hydrazones; Molecular Chaperones; Neurodegenerative Diseases; Neuroprotective Agents; Protein Aggregation, Pathological; Protein Folding; Proteostasis; Proteostasis Deficiencies; Pyrimidinones; Thiophenes; Unfolded Protein Response

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Butyrylcholinesterase; Cell Line, Tumor; Cholinesterase Inhibitors; Drug Design; Drug Evaluation, Preclinical; Humans; Inhibitory Concentration 50; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Oxidative Stress; Peptide Fragments; Phosphodiesterase Inhibitors; Protein Aggregation, Pathological; Protein Conformation; Pyrazolones; Pyrimidinones; Rivastigmine