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Pharmacological chaperones

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https://www.readbyqxmd.com/read/27881057/recent-patents-on-heat-shock-proteins-targeting-antibodies
#1
João Fernandes, Pedro Alves
BACKGROUND: Heat shock proteins (Hsp) are major chaperone molecules that have recently emerged as cancer therapeutic targets owing to their involvement in tumor cell proliferation, differentiation, invasion and metastasis. High levels of extracellular Hsp90 and Hsp70 have been closely associated with a wide range of human cancers. Accumulating evidence suggests that the pharmacological inhibition of these molecules can play a pivotal role in non-surgical cancer treatment. Efforts have been taken to develop monoclonal antibodies (mAbs) and antibody fragments targeting extracellular Hsp90 and Hsp70, alone or conjugated with standard anticancer agents, to control several types of cancer, such as breast, colon, prostate or melanoma...
November 23, 2016: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/27876883/identification-of-small-molecule-compounds-for-pharmacological-chaperone-therapy-of-aspartylglucosaminuria
#2
Antje Banning, Christina Gülec, Juha Rouvinen, Steven J Gray, Ritva Tikkanen
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27868254/extensive-functional-redundancy-in-the-regulation-of-candida-albicans-drug-resistance-and-morphogenesis-by-lysine-deacetylases-hos2-hda1-rpd3-and-rpd31
#3
Xinliu Li, Nicole Robbins, Teresa R O'Meara, Leah E Cowen
Current treatment efforts for fungal infections are hampered by the limited availability of antifungal drugs and by the emergence of drug resistance. A powerful strategy to enhance the efficacy of antifungal drugs is to inhibit the molecular chaperone Hsp90. Hsp90 governs drug resistance, morphogenesis, and virulence in a leading fungal pathogen of humans, Candida albicans. Our previous work with Saccharomyces cerevisiae established acetylation as a novel mechanism of posttranslational control of Hsp90 function in fungi...
November 21, 2016: Molecular Microbiology
https://www.readbyqxmd.com/read/27866808/combined-beta-glucosylceramide-and-ambroxol-hydrochloride-in-patients-with-gaucher-related-parkinson-disease-from-clinical-observations-to-drug-development
#4
Yuval Ishay, Ari Zimran, Jeffrey Szer, Tama Dinur, Yaron Ilan, David Arkadir
Both patients with non-neuronopathic Gaucher disease (GD) and heterozygous GBA mutation carrier are at increased risk for Parkinson disease (PD). The risk for PD in these groups does not linearly increase with glucosylceramide (GC) accumulation or with acid β-glucocerebrosidase (GCase) activity. This observation, together with other clinical systemic observations raises the possibility that extra-cellular GC actually has beneficial, anti-inflammatory, properties. Based on this hypothesis, we suggest here that the administration of supplementary oral GC to GBA carriers at risk for PD may slow inflammatory-driven secondary neuronal death...
November 12, 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27845575/hsp70-therapeutic-potential-in-acute-and-chronic-cardiac-disease-settings
#5
Bianca C Bernardo, Kate L Weeks, Natalie L Patterson, Julie R McMullen
Heat shock proteins are a family of proteins that are produced by cells in response to exposure to stressful conditions. The best studied heat shock protein is HSP70, which is known to act as a molecular chaperone to maintain cellular homeostasis and inhibit protein aggregation in response to stress. While early animal studies suggested that increasing HSP70 in the heart (using a transgenic, gene transfer or pharmacological approach) provided cardiac protection against acute cardiac stress, recent studies have found no benefit of increasing HSP70 in mouse models of chronic cardiac stress...
November 15, 2016: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/27834756/oral-pharmacological-chaperone-migalastat-compared-with-enzyme-replacement-therapy-in-fabry-disease-18-month-results-from-the-randomised-phase-iii-attract-study
#6
Derralynn A Hughes, Kathleen Nicholls, Suma P Shankar, Gere Sunder-Plassmann, David Koeller, Khan Nedd, Gerard Vockley, Takashi Hamazaki, Robin Lachmann, Toya Ohashi, Iacopo Olivotto, Norio Sakai, Patrick Deegan, David Dimmock, François Eyskens, Dominique P Germain, Ozlem Goker-Alpan, Eric Hachulla, Ana Jovanovic, Charles M Lourenco, Ichiei Narita, Mark Thomas, William R Wilcox, Daniel G Bichet, Raphael Schiffmann, Elizabeth Ludington, Christopher Viereck, John Kirk, Julie Yu, Franklin Johnson, Pol Boudes, Elfrida R Benjamin, David J Lockhart, Carrolee Barlow, Nina Skuban, Jeffrey P Castelli, Jay Barth, Ulla Feldt-Rasmussen
BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT...
November 10, 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/27829290/hsp90-inhibitors-in-the-context-of-heat-shock-and-the-unfolded-protein-response-effects-on-a-primary-canine-pulmonary-adenocarcinoma-cell-line
#7
Arin N Graner, Justin E Hellwinkel, Alex M Lencioni, Helen J Madsen, Tessa A Harland, Paul Marchando, Ger J Nguyen, Mary Wang, Laura M Russell, Lynne T Bemis, Thomas J Anchordoquy, Michael W Graner
BACKGROUND: Agents targeting HSP90 and GRP94 are seldom tested in stressed contexts such as heat shock (HS) or the unfolded protein response (UPR). Tumor stress often activates HSPs and the UPR as pro-survival mechanisms. This begs the question of stress effects on chemotherapeutic efficacy, particularly with drugs targeting chaperones such as HSP90 or GRP94. We tested the utility of several HSP90 inhibitors, including PU-H71 (targeting GRP94), on a primary canine lung cancer line under HS/UPR stress compared to control conditions...
November 9, 2016: International Journal of Hyperthermia
https://www.readbyqxmd.com/read/27816107/carbohydrate-processing-enzymes-of-the-lysosome-diseases-caused-by-misfolded-mutants-and-sugar-mimetics-as-correcting-pharmacological-chaperones
#8
Arnold E Stütz, Tanja M Wrodnigg
Lysosomal storage diseases are hereditary disorders caused by mutations on genes encoding for one of the more than fifty lysosomal enzymes involved in the highly ordered degradation cascades of glycans, glycoconjugates, and other complex biomolecules in the lysosome. Several of these metabolic disorders are associated with the absence or the lack of activity of carbohydrate-processing enzymes in this cell compartment. In a recently introduced therapy concept, for susceptible mutants, small substrate-related molecules (so-called pharmacological chaperones), such as reversible inhibitors of these enzymes, may serve as templates for the correct folding and transport of the respective protein mutant, thus improving its concentration and, consequently, its enzymatic activity in the lysosome...
2016: Advances in Carbohydrate Chemistry and Biochemistry
https://www.readbyqxmd.com/read/27813341/pharmacological-and-biological-therapeutic-strategies-for-osteogenesis-imperfecta
#9
Ronit Marom, Yi-Chien Lee, Ingo Grafe, Brendan Lee
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility, low bone mass, and bone deformities. The majority of cases are caused by autosomal dominant pathogenic variants in the COL1A1 and COL1A2 genes that encode type I collagen, the major component of the bone matrix. The remaining cases are caused by autosomal recessively or dominantly inherited mutations in genes that are involved in the post-translational modification of type I collagen, act as type I collagen chaperones, or are members of the signaling pathways that regulate bone homeostasis...
November 3, 2016: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
https://www.readbyqxmd.com/read/27788225/identification-of-an-allosteric-binding-site-on-human-lysosomal-alpha-galactosidase-opens-the-way-to-new-pharmacological-chaperones-for-fabry-disease
#10
Valentina Citro, Jorge Peña-García, Helena den-Haan, Horacio Pérez-Sánchez, Rosita Del Prete, Ludovica Liguori, Chiara Cimmaruta, Jan Lukas, Maria Vittoria Cubellis, Giuseppina Andreotti
Personalized therapies are required for Fabry disease due to its large phenotypic spectrum and numerous different genotypes. In principle, missense mutations that do not affect the active site could be rescued with pharmacological chaperones. At present pharmacological chaperones for Fabry disease bind the active site and couple a stabilizing effect, which is required, to an inhibitory effect, which is deleterious. By in silico docking we identified an allosteric hot-spot for ligand binding where a drug-like compound, 2,6-dithiopurine, binds preferentially...
2016: PloS One
https://www.readbyqxmd.com/read/27774737/pharmacological-chaperoning-a-potential-treatment-for-pmm2-cdg
#11
Patricia Yuste-Checa, Sandra Brasil, Alejandra Gámez, Jarl Underhaug, Lourdes R Desviat, Magdalena Ugarte, Celia Pérez-Cerdá, Aurora Martinez, Belén Pérez
The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low-molecular-weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2...
October 24, 2016: Human Mutation
https://www.readbyqxmd.com/read/27750150/-5ar-5a-c-pentyl-4-epi-isofagomine-a-powerful-inhibitor-of-lysosomal-%C3%AE-galactosidase-and-a-remarkable-chaperone-for-mutations-associated-with-gm1-gangliosidosis-and-morquio-disease-type-b
#12
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
https://www.readbyqxmd.com/read/27744182/rapid-preparation-of-3r-4s-5r-polyhydroxylated-pyrrolidine-based-libraries-to-discover-a-pharmacological-chaperone-for-treatment-of-fabry-disease
#13
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
https://www.readbyqxmd.com/read/27729867/targeting-heat-shock-proteins-mitigates-ventilator-induced-diaphragm-muscle-dysfunction-in-an-age-dependent-manner
#14
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
https://www.readbyqxmd.com/read/27720586/endoplasmic-reticulum-proteostasis-influences-the-oligomeric-state-of-an-amyloidogenic-protein-secreted-from-mammalian-cells
#15
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
https://www.readbyqxmd.com/read/27719636/rnf5-dab2-and-friends-novel-drug-targets-for-cystic-fibrosis
#16
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
https://www.readbyqxmd.com/read/27707963/disruption-of-protein-processing-in-the-endoplasmic-reticulum-of-dyt1-knock-in-mice-implicates-novel-pathways-in-dystonia-pathogenesis
#17
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
https://www.readbyqxmd.com/read/27706135/the-epichaperome-is-an-integrated-chaperome-network-that-facilitates-tumour-survival
#18
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
https://www.readbyqxmd.com/read/27702699/targeting-chaperones-heat-shock-factor-1-and-unfolded-protein-response-promising-therapeutic-approaches-for-neurodegenerative-disorders
#19
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
https://www.readbyqxmd.com/read/27678341/editorial-thematic-issue-targeting-conformational-diseases-with-natural-and-pharmacological-chaperones
#20
EDITORIAL
Angel Luis Pey
No abstract text is available yet for this article.
2016: Current Drug Targets
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