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Pharmacological chaperones

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https://www.readbyqxmd.com/read/28916430/therapeutic-approaches-to-cftr-dysfunction-from-discovery-to-drug-development
#1
Hongyu Li, Emanuela Pesce, David N Sheppard, Ashvani K Singh, Nicoletta Pedemonte
Cystic fibrosis (CF) mutations have complex effects on the cystic fibrosis transmembrane conductance regulator (CFTR) protein. They disrupt its processing to and stability at the plasma membrane and function as an ATP-gated Cl(-) channel. Here, we review therapeutic strategies to overcome defective CFTR processing and stability. Because CF mutations have multiple impacts on the assembly of CFTR protein, combination therapy with several pharmacological chaperones is likely to be required to rescue mutant CFTR expression at the plasma membrane...
September 12, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28911813/functional-dynamics-in-cyclic-nucleotide-signaling-and-amyloid-inhibition
#2
REVIEW
Bryan VanSchouwen, Rashik Ahmed, Julijana Milojevic, Giuseppe Melacini
It is now established that understanding the molecular basis of biological function requires atomic resolution maps of both structure and dynamics. Here, we review several illustrative examples of functional dynamics selected from our work on cyclic nucleotide signaling and amyloid inhibition. Although fundamentally diverse, a central aspect common to both fields is that function can only be rationalized by considering dynamic equilibria between distinct states of the accessible free energy landscape. The dynamic exchange between ground and excited states of signaling proteins is essential to explain auto-inhibition and allosteric activation...
September 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28903474/nitric-oxide-heat-shock-protein-axis-in-menopausal-hot-flushes-neglected-metabolic-issues-of-chronic-inflammatory-diseases-associated-with-deranged-heat-shock-response
#3
Antônio Azambuja Miragem, Paulo Ivo Homem de Bittencourt
BACKGROUND: Although some unequivocal underlying mechanisms of menopausal hot flushes have been demonstrated in animal models, the paucity of similar approaches in humans impedes further mechanistic outcomes. Human studies might show some as yet unexpected physiological mechanisms of metabolic adaptation that permeate the phase of decreased oestrogen levels in both symptomatic and asymptomatic women. This is particularly relevant because both the severity and time span of hot flushes are associated with increased risk of chronic inflammatory disease...
September 1, 2017: Human Reproduction Update
https://www.readbyqxmd.com/read/28900272/from-malaria-to-cancer-computational-drug-repositioning-of-amodiaquine-using-plip-interaction-patterns
#4
Sebastian Salentin, Melissa F Adasme, Jörg C Heinrich, V Joachim Haupt, Simone Daminelli, Yixin Zhang, Michael Schroeder
Drug repositioning identifies new indications for known drugs. Here we report repositioning of the malaria drug amodiaquine as a potential anti-cancer agent. While most repositioning efforts emerge through serendipity, we have devised a computational approach, which exploits interaction patterns shared between compounds. As a test case, we took the anti-viral drug brivudine (BVDU), which also has anti-cancer activity, and defined ten interaction patterns using our tool PLIP. These patterns characterise BVDU's interaction with its target s...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28898759/cuprous-oxide-nanoparticles-trigger-er-stress-induced-apoptosis-by-regulating-copper-trafficking-and-overcoming-resistance-to-sunitinib-therapy-in-renal-cancer
#5
Qiwei Yang, Ye Wang, Qing Yang, Yi Gao, Xiaopeng Duan, Qingcheng Fu, Chuanmin Chu, Xiuwu Pan, Xingang Cui, Yinghao Sun
While the current standard first-line treatment for advanced renal cell carcinoma (RCC) is sunitinib, patients inevitably develop resistance to this drug. However, the rapid development of nanotechnology has provided emerging techniques for the treatment of advanced tumours, including RCC. In our previous research, cuprous oxide nanoparticles (CONPs) showed ideal anti-tumour effects and low systemic toxicity. While many inorganic nanomedicines, including CONPs, have similar pharmacological effects, their detailed mechanisms remain unknown...
September 5, 2017: Biomaterials
https://www.readbyqxmd.com/read/28890376/an-unfolding-story-small-molecules-remedy-misfolded-monoamine-transporters
#6
Ameya Kasture, Thomas Stockner, Michael Freissmuth, Sonja Sucic
The key role of monoamine transporters is to take up neurotransmitters from the synaptic cleft and rapidly terminate neurotransmission. Monoamine transporters begin their journey by folding in the endoplasmic reticulum. Upon achieving their natively-folded state, the oligomerized transporters engage the coat protein complex II machinery and exit the endoplasmic reticulum compartment in a concentrative fashion. The transporters are subsequently sorted in the endoplasmic reticulum-Golgi intermediate complex and the Golgi apparatus, prior to reaching their pivotal site of action at the plasma membrane...
September 7, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28871306/introduction-to-sigma-proteins-evolution-of-the-concept-of-sigma-receptors
#7
Felix J Kim
For over 40 years, scientists have endeavored to understand the so-called sigma receptors. During this time, the concept of sigma receptors has continuously and significantly evolved. With thousands of publications on the subject, these proteins have been implicated in various diseases, disorders, and physiological processes. Nevertheless, we are just beginning to understand what sigma proteins do and how they work. Two subtypes have been identified, Sigma1 and Sigma2. Whereas Sigma1 (also known as sigma-1 receptor, Sig1R, σ1 receptor, and several other names) was cloned over 20 years ago, Sigma2 (sigma-2 receptor, σ2 receptor) was cloned very recently and had remained a pharmacologically defined entity...
September 5, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28869836/toward-a-generalized-computational-workflow-for-exploiting-transient-pockets-as-new-targets-for-small-molecule-stabilizers-application-to-the-homogentisate-1-2-dioxygenase-mutants-at-the-base-of-rare-disease-alkaptonuria
#8
Andrea Bernini, Silvia Galderisi, Ottavia Spiga, Giulia Bernardini, Neri Niccolai, Fabrizio Manetti, Annalisa Santucci
Alkaptonuria (AKU) is an inborn error of metabolism where mutation of homogentisate 1,2-dioxygenase (HGD) gene leads to a deleterious or misfolded product with subsequent loss of enzymatic degradation of homogentisic acid (HGA) whose accumulation in tissues causes ochronosis and degeneration. There is no licensed therapy for AKU. Many missense mutations have been individuated as responsible for quaternary structure disruption of the native hexameric HGD. A new approach to the treatment of AKU is here proposed aiming to totally or partially rescue enzyme activity by targeting of HGD with pharmacological chaperones, i...
August 25, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28863358/from-dual-binding-site-acetylcholinesterase-inhibitors-to-allosteric-modulators-a-new-avenue-for-disease-modifying-drugs-in-alzheimer-s-disease
#9
Talita P C Chierrito, Susimaire Pedersoli-Mantoani, Carlos Roca, Carlos Requena, Victor Sebastian-Perez, Willian O Castillo, Natalia C S Moreira, Concepción Pérez, Elza T Sakamoto-Hojo, Catarina S Takahashi, Jesús Jiménez-Barbero, F Javier Cañada, Nuria E Campillo, Ana Martinez, Ivone Carvalho
The lack of an effective treatment for Alzheimer' disease (AD), an increasing prevalence and severe neurodegenerative pathology boost medicinal chemists to look for new drugs. Currently, only acethylcholinesterase (AChE) inhibitors and glutamate antagonist have been approved to the palliative treatment of AD. Although they have a short-term symptomatic benefits, their clinical use have revealed important non-cholinergic functions for AChE such its chaperone role in beta-amyloid toxicity. We propose here the design, synthesis and evaluation of non-toxic dual binding site AChEIs by hybridization of indanone and quinoline heterocyclic scaffolds...
August 26, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28857617/recent-advances-and-novel-treatments-for-sphingolipidoses
#10
Christoph Arenz
Sphingolipidoses are genetically inherited diseases in which genetic mutations lead to functional deficiencies in the enzymes needed for lysosomal degradation of sphingolipid substrates. As a consequence, nondegradable lipids enrich in the lysosomes and lead to fatal pathological phenotypes in affected individuals. In this review, different drug-based treatment strategies including enzyme replacement therapy and substrate reduction therapy are discussed. A special focus is on the concept of pharmacological chaperones, one of which recently acquired clinical approval within the EU...
August 31, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28837626/trehalose-improves-traumatic-brain-injury-induced-cognitive-impairment
#11
Stuart D Portbury, Dominic J Hare, David I Finkelstein, Paul A Adlard
Traumatic brain Injury (TBI) is a significant cause of death and long-term disability for which there are currently no effective pharmacological treatment options. In this study then, we utilized a mouse model of TBI to assess the therapeutic potential of the stable disaccharide trehalose, which is known to protect against oxidative stress, increase levels of chaperone molecules and enhance autophagy. Furthermore, trehalose has demonstrated neuroprotective properties in numerous animal models and has been proposed as a potential treatment for neurodegeneration...
2017: PloS One
https://www.readbyqxmd.com/read/28797116/calcium-imaging-with-genetically-encoded-sensor-case12-facile-analysis-of-%C3%AE-7-%C3%AE-9-nachr-mutants
#12
Irina Shelukhina, Ekaterina Spirova, Denis Kudryavtsev, Lucy Ojomoko, Markus Werner, Christoph Methfessel, Michael Hollmann, Victor Tsetlin
Elucidation of the structural basis of pharmacological differences for highly homologous α7 and α9 nicotinic acetylcholine receptors (nAChRs) may shed light on their involvement in different physiological functions and diseases. Combination of site-directed mutagenesis and electrophysiology is a powerful tool to pinpoint the key amino-acid residues in the receptor ligand-binding site, but for α7 and α9 nAChRs it is complicated by their poor expression and fast desensitization. Here, we probed the ligand-binding properties of α7/α9 nAChR mutants by a proposed simple and fast calcium imaging method...
2017: PloS One
https://www.readbyqxmd.com/read/28763689/investigation-of-novel-pharmacological-chaperones-for-gaucher-disease
#13
Buge Yilmazer, Z Begum Yagci, Emre Bakar, Burcu Ozden, Kutlu Ulgen, Elif Ozkirimli
Beta-Glucocerebrosidase (GBA) is a lysosomal protein that is responsible for the hydrolysis of glycosylceramide into glucose and ceramide. Mutations in GBA lead to the accumulation of glycosylceramide in the lysosome causing an enlargement of the spleen and the liver and skeletal deformations. This disease is called Gaucher Disease. Enzyme replacement therapies and substrate reduction methods that are used to treat Gaucher Disease fail when the disease is neuropathic because they fail to pass the blood brain barrier...
July 20, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28740222/primary-fibroblasts-from-csp%C3%AE-mutation-carriers-recapitulate-hallmarks-of-the-adult-onset-neuronal-ceroid-lipofuscinosis
#14
Bruno A Benitez, Mark S Sands
Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28739485/hsp90-is-necessary-for-the-ack1-dependent-phosphorylation-of-stat1-and-stat3
#15
Nisintha Mahendrarajah, Marina E Borisova, Sigrid Reichardt, Maren Godmann, Andreas Sellmer, Siavosh Mahboobi, Andrea Haitel, Katharina Schmid, Lukas Kenner, Thorsten Heinzel, Petra Beli, Oliver H Krämer
Signal transducers and activators of transcription (STATs) are latent, cytoplasmic transcription factors. Janus kinases (JAKs) and activated CDC42-associated kinase-1 (ACK1/TNK2) catalyse the phosphorylation of STAT1 and the expression of its target genes. Here we demonstrate that catalytically active ACK1 promotes the phosphorylation and nuclear accumulation of STAT1 in transformed kidney cells. These processes are associated with STAT1-dependent gene expression and an interaction between endogenous STAT1 and ACK1...
November 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28717943/a-pyrrole-based-natural-small-molecule-mitigates-hsp90-expression-in-mda-mb-231-cells-and-inhibits-tumor-angiogenesis-in-mice-by-inactivating-hsf-1
#16
K C Rashmi, H S Atreya, M Harsha Raj, Bharathi P Salimath, H S Aparna
Heat shock proteins (HSPs), molecular chaperones, are crucial for the cancer cells to facilitate proper functioning of various oncoproteins involved in cell survival, proliferation, migration, and tumor angiogenesis. Tumor cells are said to be "addicted" to HSPs. HSPs are overexpressed in many cancers due to upregulation of transcription factor Heat-shock factor 1 (HSF-1), the multifaceted master regulator of heat shock response. Therefore, pharmacological targeting of HSPs via HSF-1 is an effective strategy to treat malignant cancers like triple negative breast cancer...
July 17, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28697448/in-silico-analyses-of-the-effects-of-a-point-mutation-and-a-pharmacological-chaperone-on-the-thermal-fluctuation-of-phenylalanine-hydroxylase
#17
Daichi Hayakawa, Noriyuki Yamaotsu, Izumi Nakagome, Shin-Ichiro Ozawa, Tomoki Yoshida, Shuichi Hirono
Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism due to mutations in phenylalanine hydroxylase (PAH). Recently, small compounds, known as pharmacological chaperones (PhCs), have been identified that restore the enzymatic activity of mutant PAHs. Understanding the mechanism of the reduction in enzymatic activity due to a point mutation in PAH and its restoration by PhC binding is important for the design of more effective PhC drugs. Thermal fluctuations of an enzyme can alter its activity...
September 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/28674946/toxin-transport-by-a-b-type-of-toxins-in-eukaryotic-target-cells-and-its-inhibition-by-positively-charged-heterocyclic-molecules
#18
Roland Benz, Holger Barth
A-B types of toxins are among the most potent bacterial protein toxins produced by gram-positive bacteria. Prominent examples are the tripartite anthrax toxin of Bacillus anthracis and the different A-B type clostridial toxins that are the causative agents of severe human and animal diseases and could serve as biological weapons. The components of all these toxins comprise one binding/transport (B) subunit and one or two separate, non-linked enzymatically active (A) subunits. The A and B subunits are separately produced and secreted by the pathogenic gram-positive bacteria and must assemble on the surface of eukaryotic target cells to form biologically active toxin complexes...
July 4, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28671287/protein-misfolding-diseases-prospects-of-pharmacological-treatment
#19
REVIEW
Alejandra Gámez, Patricia Yuste-Checa, Sandra Brasil, Álvaro Briso-Montiano, Lourdes R Desviat, Magdalena Ugarte, Celia Pérez-Cerdá, Belén Pérez
Protein misfolding has been linked to numerous inherited diseases. Loss- and gain-of-function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases...
July 3, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28652811/structure-based-virtual-screening-and-molecular-docking-for-the-identification-of-potential-multi-targeted-inhibitors-against-breast-cancer
#20
Zeeshan Yousuf, Kanzal Iman, Nauman Iftikhar, Muhammad Usman Mirza
Breast cancer is characterized by an uncontrolled growth of cells in breast tissue. Genes that foster cell growth in breast cells are overexpressed, giving rise to breast tumors. The identification of effective inhibitors represents a rational chemopreventive strategy. The current in silico study provides a pharmacoinformatic approach for the identification of active compounds against a co-chaperone HSP90 and the human epidermal growth factor receptors EGFR and HER2/neu receptor. The elevated levels of expression of these target proteins have been documented in breast cancer...
2017: Breast Cancer: Targets and Therapy
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