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Pharmacological chaperones

Sophie Front, Anna Biela-Banaś, Patricie Burda, Diana Ballhausen, Katsumi Higaki, Anna Caciotti, Amelia Morrone, Julie Charollais-Thoenig, Estelle Gallienne, Stéphane Demotz, Olivier R Martin
This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal β-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human β-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC50 = 8 nM, 30× more potent than 4-epi-isofagomine at pH 7...
September 29, 2016: European Journal of Medicinal Chemistry
Wei-Chieh Cheng, Jen-Hon Wang, Wen-Yi Yun, Huang-Yi Li, Jia-Ming Hu
The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells...
October 5, 2016: European Journal of Medicinal Chemistry
Hannah Ogilvie, Nicola Cacciani, Hazem Akkad, Lars Larsson
Intensive care unit (ICU) patients are often overtly subjected to mechanical ventilation and immobilization, which leads to impaired limb and respiratory muscle function. The latter, termed ventilator-induced diaphragm dysfunction (VIDD) has recently been related to compromised heat shock protein (Hsp) activation. The administration of a pharmacological drug BGP-15 acting as a Hsp chaperone co-inducer has been found to partially alleviate VIDD in young rats. Considering that the mean age in the ICU is increasing, we aimed to explore whether the beneficial functional effects are also present in old rats...
2016: Frontiers in Physiology
John J Chen, Joseph C Genereux, Eul Hyun Suh, Vincent F Vartabedian, Bibiana Rius, Song Qu, Maria T A Dendle, Jeffery W Kelly, R Luke Wiseman
Transthyretin (TTR) is a tetrameric serum protein associated with multiple systemic amyloid diseases. In these disorders, TTR aggregates in extracellular environments through a mechanism involving rate-limiting dissociation of the tetramer to monomers, which then misfold and aggregate into soluble oligomers and amyloid fibrils that induce toxicity in distal tissues. Using an assay established herein, we show that highly destabilized, aggregation-prone TTR variants are secreted as both native tetramers and non-native conformations that accumulate as high-molecular-weight oligomers...
October 20, 2016: Cell Chemical Biology
Elvira Sondo, Emanuela Pesce, Valeria Tomati, Monica Marini, Nicoletta Pedemonte
BACKGROUND: Deletion of phenylalanine 508 is the most frequent mutation causing cystic fibrosis. It causes multiple defects: 1) misfolding of the protein causing retention at the ER (processing defect); 2) reduced channel activity (gating defect); 3) reduced plasma membrane residency time due to increased internalization rate and defective recycling. METHODS: Druggability of F508del-CFTR was demonstrated by several studies. Correctors are molecules able to improve maturation and trafficking to the membrane of F508del-CFTR...
October 6, 2016: Current Pharmaceutical Design
Genevieve Beauvais, Nicole M Bode, Jaime L Watson, Hsiang Wen, Kevin A Glenn, Hiroyuki Kawano, N Charles Harata, Michelle E Ehrlich, Pedro Gonzalez-Alegre
: Dystonia type 1 (DYT1) is a dominantly inherited neurological disease caused by mutations in TOR1A, the gene encoding the endoplasmic reticulum (ER)-resident protein torsinA. Previous work mostly completed in cell-based systems suggests that mutant torsinA alters protein processing in the secretory pathway. We hypothesized that inducing ER stress in the mammalian brain in vivo would trigger or exacerbate mutant torsinA-induced dysfunction. To test this hypothesis, we crossed DYT1 knock-in with p58(IPK)-null mice...
October 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Anna Rodina, Tai Wang, Pengrong Yan, Erica DaGama Gomes, Mark P S Dunphy, Nagavarakishore Pillarsetty, John Koren, John F Gerecitano, Tony Taldone, Hongliang Zong, Eloisi Caldas-Lopes, Mary Alpaugh, Adriana Corben, Matthew Riolo, Brad Beattie, Christina Pressl, Radu I Peter, Chao Xu, Robert Trondl, Hardik J Patel, Fumiko Shimizu, Alexander Bolaender, Chenghua Yang, Palak Panchal, Mohammad F Farooq, Sarah Kishinevsky, Shanu Modi, Oscar Lin, Feixia Chu, Sujata Patil, Hediye Erdjument-Bromage, Pat Zanzonico, Clifford Hudis, Lorenz Studer, Gail J Roboz, Ethel Cesarman, Leandro Cerchietti, Ross Levine, Ari Melnick, Steven M Larson, Jason S Lewis, Monica L Guzman, Gabriela Chiosis
Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis...
October 5, 2016: Nature
Shambhunath Bose, Jungsook Cho
Protein misfolding, which is known to cause several serious diseases, is an emerging field that addresses multiple therapeutic areas. Misfolding of a disease-specific protein in the central nervous system ultimately results in the formation of toxic aggregates that may accumulate in the brain, leading to neuronal cell death and dysfunction, and associated clinical manifestations. A large number of neurodegenerative diseases in humans, including Alzheimer's, Parkinson's, Huntington's, and prion diseases, are primarily caused by protein misfolding and aggregation...
October 1, 2016: Ageing Research Reviews
Angel Luis Pey
No abstract text is available yet for this article.
2016: Current Drug Targets
Martina Gaggl, Gere Sunder-Plassmann
No abstract text is available yet for this article.
November 2016: Nature Reviews. Nephrology
Eva-Maria Kuech, Graham Brogden, Hassan Y Naim
Lysosomal storage disorders are a heterogeneous group of more than 50 distinct inborn metabolic diseases affecting about 1 in 5000 to 7000 live births. The diseases often result from mutations followed by functional deficiencies of enzymes or transporters within the acidic environment of the lysosome, which mediate the degradation of a wide subset of substrates, including glycosphingolipids, glycosaminoglycans, cholesterol, glycogen, oligosaccharides, peptides and glycoproteins, or the export of the respective degradation products from the lysosomes...
September 21, 2016: Biochimie
Sara D Reis, Brígida R Pinho, Jorge M A Oliveira
Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs and suggests different interactions with the cellular proteostasis machinery...
September 22, 2016: Molecular Neurobiology
Hyun-Jin Kang, Yunxi Cui, Holly Yin, Amy Scheid, William P D Hendricks, Jessica Schmidt, Aleksandar Sekulic, Deming Kong, Jeffrey M Trent, Vijay Gokhale, Hanbin Mao, Laurence H Hurley
Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wild-type (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy...
October 5, 2016: Journal of the American Chemical Society
Adriana Carol Eleonora Graziano, Giovanna Pannuzzo, Rosanna Avola, Venera Cardile
Krabbe's disease (KD) is an autosomal recessive, neurodegenerative disorder. It is classified among the lysosomal storage diseases (LSDs). It was first described in , but the genetic defect for the galactocerebrosidase (GALC) gene was not discovered until the beginning of the 1970s, 20 years before the GALC cloning. Recently, in 2011, the crystal structures of the GALC enzyme and the GALC-product complex were obtained. For this, compared with other LSDs, the research on possible therapeutic interventions is much more recent...
November 2016: Journal of Neuroscience Research
Samantha J Spratley, Janet E Deane
Missense mutations in the lysosomal hydrolase β-galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics...
November 2016: Journal of Neuroscience Research
Cristina Contreras, Ismael González-García, Patricia Seoane-Collazo, Noelia Martínez-Sánchez, Laura Liñares-Pose, Eva Rial-Pensado, Johan Fernø, Manuel Tena-Sempere, Núria Casals, Carlos Diéguez, Rubén Nogueiras, Miguel López
The chaperone GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to ER stress. The aim of this study was to investigate the role of hypothalamic GRP78 on energy balance, with particular interest on thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and thapsigargin-treated rats and by combining metabolic, histologic, physiologic, pharmacologic, thermographic and molecular techniques, we studied the effect of genetic manipulation of hypothalamic GRP78...
September 15, 2016: Diabetes
Julia M Eckl, Marina Daake, Sebastian Schwartz, Klaus Richter
The molecular chaperone Hsp90 and its cofactor Cdc37 are required for the stability of protein kinases in the cellular environment. Upon pharmacological inhibition of Hsp90, the Hsp90-dependent kinases are degraded quickly by the proteasome. Clear physiological evidence for the formation of heterooligomeric complexes between the chaperone system and its kinase clients exist, but the mechanisms of client processing are still enigmatic. Here, we investigate the interaction of the chaperone system with a stabilized fragment of the Hsp90-dependent protein kinase B-Raf (sB-Raf)...
October 9, 2016: Journal of Molecular Biology
Yann Desfougères, R Uta Gerasimaitė, Henning Jacob Jessen, Andreas Mayer
SPX domains control phosphate homeostasis in eukaryotes. Ten genes in yeast encode SPX-containing proteins, among which YDR089W is the only one of unknown function. Here, we show that YDR089W encodes a novel subunit of the vacuole transporter chaperone (VTC) complex that produces inorganic polyphosphate (polyP). The polyP synthesis transfers inorganic phosphate (Pi) from the cytosol into the acidocalcisome- and lysosome-related vacuoles of yeast, where it can be released again. It was therefore proposed for buffer changes in cytosolic Pi concentration (Thomas, M...
October 14, 2016: Journal of Biological Chemistry
Yohei Sato, Hiroshi Kobayashi, Takashi Higuchi, Yohta Shimada, Hiroyuki Ida, Toya Ohashi
Pompe disease (PD) is a lysosomal disorder caused by acid α-glucosidase (GAA) deficiency. Progressive muscular weakness is the major symptom of PD, and enzyme replacement therapy can improve the clinical outcome. However, to achieve a better clinical outcome, alternative therapeutic strategies are being investigated, including gene therapy and pharmacological chaperones. We previously used lentiviral vector-mediated GAA gene transfer in PD patient-specific induced pluripotent stem cells. Some therapeutic efficacy was observed, although glycogen accumulation was not normalized...
2016: Molecular Therapy. Methods & Clinical Development
Pieter Beerepoot, Vincent M Lam, Ali Salahpour
A number of pathological conditions have been linked to mutations in the dopamine transporter gene, including hereditary dopamine transporter deficiency syndrome (DTDS). DTDS is a rare condition that is caused by autosomal recessive loss-of-function mutations in the dopamine transporter (DAT), which often affects transporter trafficking and folding. We examined the possibility of using pharmacological chaperones of DAT to rescue DTDS mutations. After screening a set of known DAT ligands for their ability to increase DAT surface expression, we found that bupropion and ibogaine increased DAT surface expression, whereas others, including cocaine and methylphenidate, had no effect...
October 14, 2016: Journal of Biological Chemistry
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