subject:(Pharmacological chaperones)

University of Miami

1. Morton, Terrell R. Increased Acetylcholinesterase Expression Through Pharmacological Chaperones.

Degree: MS, Neuroscience (Medicine), 2013, University of Miami

URL: https://scholarlyrepository.miami.edu/oa_theses/443

► Acetylcholinesterase (AChE) is the enzyme that functions in terminating neurotransmission by hydrolyzing acetylcholine (ACh) in the central and peripheral nervous systems. Like all exportable… (more)

▼ Acetylcholinesterase (AChE) is the enzyme that functions in terminating neurotransmission by hydrolyzing acetylcholine (ACh) in the central and peripheral nervous systems. Like all exportable proteins, AChE is synthesized on the rough endoplasmic reticulum (RER), processed in the Golgi apparatus, and externalized at the cell surface following vesicular transport. Interestingly, less than one quarter of the newly synthesized AChE is correctly folded, becomes catalytically active, and transported to the cell surface. The remainder of the molecules are retained in the cell and targeted to the endoplasmic reticulum associated degradation (ERAD) system. How cells distinguish between these two possibilities is unknown. To answer this question, we sought to alter the balance between correctly folded and incorrectly folded AChE molecules. Pharmacological agents such as donepezil, galantamine, and tacrine have been used in many studies demonstrating their ability to inhibit AChE activity. These agents function by binding electrostatically to the active site of AChE preventing the hydrolysis of ACh, therefore modulating synaptic transmission by increasing ACh in the synaptic cleft. Using biochemical and cell biological techniques including enzymatic assays, velocity sedimentation, and Western blot analysis, we demonstrated increased AChE activity in Human Embryonic Kidney 293 cells (HEK293) expressing mouse AChE and in an in vivo mouse model. AChE activity was measured in vitro from newly synthesized AChE molecules generated by the incubation of the cells with these pharmacological agents after total AChE inhibition with an irreversible organophosphate, diisofluropropylphosphate. Differences in AChE activity were measured as an increase over baseline in the mouse model. These results suggest that through the interaction with the catalytic site, Acetylcholinesterase inhibitors (AChEIs) can increase enzyme activity by stabilizing newly synthesized molecules within the endoplasmic reticulum, thus altering the balance between correctly and incorrectly folded enzyme. This provides a mechanism for using small molecules such as AChEIs as a potential pharmacological chaperone, increasing catalytically active AChE through protein stabilization. Advisors/Committee Members: Richard L. Rotundo, Coleen M. Atkins, Grace Zhai, Arun Malhotra.

Subjects/Keywords: Acetylcholinesterase; Pharmacological Chaperones; Donepezil; Acetylcholinesterase Inhibitors; Galantamine; Tacrine

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APA (6^th Edition):

Morton, T. R. (2013). Increased Acetylcholinesterase Expression Through Pharmacological Chaperones. (Thesis). University of Miami. Retrieved from https://scholarlyrepository.miami.edu/oa_theses/443

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Morton, Terrell R. “Increased Acetylcholinesterase Expression Through Pharmacological Chaperones.” 2013. Thesis, University of Miami. Accessed January 17, 2021. https://scholarlyrepository.miami.edu/oa_theses/443.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Morton, Terrell R. “Increased Acetylcholinesterase Expression Through Pharmacological Chaperones.” 2013. Web. 17 Jan 2021.

Vancouver:

Morton TR. Increased Acetylcholinesterase Expression Through Pharmacological Chaperones. [Internet] [Thesis]. University of Miami; 2013. [cited 2021 Jan 17]. Available from: https://scholarlyrepository.miami.edu/oa_theses/443.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Morton TR. Increased Acetylcholinesterase Expression Through Pharmacological Chaperones. [Thesis]. University of Miami; 2013. Available from: https://scholarlyrepository.miami.edu/oa_theses/443

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Toronto

2. Beerepoot, Pieter Claus. Pharmacological Chaperones of the Dopamine Transporter: A Strategy for Increasing Function of Wild Type and Mutant Transporter.

Degree: PhD, 2017, University of Toronto

URL: http://hdl.handle.net/1807/78039

► The dopamine transporter (DAT) is a membrane protein that is essential for regulating signaling and intracellular stores of the neurotransmitter dopamine. An array of pathological… (more)

▼ The dopamine transporter (DAT) is a membrane protein that is essential for regulating signaling and intracellular stores of the neurotransmitter dopamine. An array of pathological conditions have been linked to mutations in the dopamine transporter gene, including ADHD, bipolar disorder, autism, and dopamine transporter deficiency syndrome (DTDS). DTDS is of particular interest, because it is exclusively caused by autosomal recessive loss-of-function mutations in the dopamine transporter (DAT), resulting in a debilitating pediatric movement disorder that is eventually fatal. The majority of DTDS DAT mutations disrupt DAT function by affecting folding and maturation of the transporter. Pharmacological chaperones have previously been used to rescue mutations in other membrane proteins, and we therefore examined the possibility of using pharmacological chaperones to rescue DTDS mutations. We developed a DAT surface expression assay in order to screen candidate compounds for potential pharmacological chaperone activity. After screening a set of known DAT ligands, we found that the DAT inhibitors bupropion and ibogaine increased DAT surface expression, whereas other inhibitors, including cocaine and methylphenidate, had no effect. The effect appears to be associated with stabilization of an inward- facing or occluded, as opposed to an outward-facing conformation of the DAT. Bupropion and ibogaine increased wild type DAT protein levels, demonstrating that drug effects were not merely due to protein trafficking. Bupropion and ibogaine also promoted maturation of the endoplasmic reticulum (ER)-retained DAT mutant K590A, which could be blocked by inhibiting ER to Golgi transport. Furthermore, bupropion decreased the half-life of immature ER-retained K590A DAT in cycloheximide chase assays. The data suggest that bupropion and ibogaine promote maturation of DAT by acting as pharmacological chaperones in the ER. Importantly, both drugs rescue DAT maturation and functional activity of a subset of DTDS-associated DAT mutants. Tests of pharmacological chaperoning of DAT in mice were not conclusive, and future studies will have to assess in vivo activity of bupropion in a true DTDS mouse model. Together, these results are the first demonstration of pharmacological chaperoning of DAT, and suggest this may be a viable approach to increase DAT levels in DTDS and other conditions associated with reduced DAT function. Advisors/Committee Members: Salahpour, Ali, Pharmacology.

Subjects/Keywords: Dopamine; Dopamine transporter deficiency syndrome; Pharmacological chaperones; Protein folding; 0419

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Beerepoot, P. C. (2017). Pharmacological Chaperones of the Dopamine Transporter: A Strategy for Increasing Function of Wild Type and Mutant Transporter. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/78039

Chicago Manual of Style (16^th Edition):

Beerepoot, Pieter Claus. “Pharmacological Chaperones of the Dopamine Transporter: A Strategy for Increasing Function of Wild Type and Mutant Transporter.” 2017. Doctoral Dissertation, University of Toronto. Accessed January 17, 2021. http://hdl.handle.net/1807/78039.

MLA Handbook (7^th Edition):

Beerepoot, Pieter Claus. “Pharmacological Chaperones of the Dopamine Transporter: A Strategy for Increasing Function of Wild Type and Mutant Transporter.” 2017. Web. 17 Jan 2021.

Vancouver:

Beerepoot PC. Pharmacological Chaperones of the Dopamine Transporter: A Strategy for Increasing Function of Wild Type and Mutant Transporter. [Internet] [Doctoral dissertation]. University of Toronto; 2017. [cited 2021 Jan 17]. Available from: http://hdl.handle.net/1807/78039.

Council of Science Editors:

Beerepoot PC. Pharmacological Chaperones of the Dopamine Transporter: A Strategy for Increasing Function of Wild Type and Mutant Transporter. [Doctoral Dissertation]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/78039

3. Guce, Abigail Ida. Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones.

Degree: PhD, Chemistry, 2010, U of Massachusetts : PhD

URL: https://scholarworks.umass.edu/open_access_dissertations/202

► Human α-galactosidase (α-GAL; EC 3.2.1.22) is a lysosomal enzyme that hydrolyzes of terminal alpha-linked galactosyl residue of glycosphingolipids. Deficiencies in α-GAL leads to Fabry… (more)

▼ Human α-galactosidase (α-GAL; EC 3.2.1.22) is a lysosomal enzyme that hydrolyzes of terminal alpha-linked galactosyl residue of glycosphingolipids. Deficiencies in α-GAL leads to Fabry disease, which is characterized by the build-up of globotriaosylceramide and other neutral substrates in cells, ultimately leading to a multi-systemic organ failure in patients. Hundreds of distinct mutations have been found in the α-GAL gene of Fabry disease patients. One current treatment for Fabry disease is Enzyme Replacement Therapy (ERT), which restores the missing α-GAL function. An alternative treatment, called Pharmacological Chaperone Therapy (PCT), utilizes a small molecule substrate analogue, 1-deoxygalactonojirimycin (DGJ). In order to better understand molecular basis of Fabry disease, this work addresses structural and mechanistic studies of the α-GAL glycoprotein. First, we have determined crystal structures of each stage in the catalytic mechanism of the α-GAL enzymatic reaction. These studies reveal a novel strained conformation of the sugar when it is covalently bound to the enzyme. Second, we examine the molecular mechanism of chaperoning by pharmacological chaperones. A combination of biochemical and biophysical approaches reveals that the high potency of the DGJ chaperone is due to an interaction with α-GAL residue D170. Third, we have investigated mutant α-GAL proteins for their response to pharmacological chaperones, leading to a set of structure-based rules for predicting the effect of pharmacological chaperone on every Fabry disease patient. Fourth, we use rational design approaches to interconvert the specificity of α-GAL into that of a related enzyme, α-N-acetylgalactosaminidase (α-NAGAL). Structural and enzymatic experiments show that the engineered enzyme contains new substrate specificity, as predicted by the design. The structural and mechanistic details we present in this thesis provide better understanding of the catalysis of the human α-galactosidase enzyme as well as define the molecular basis for pharmacological chaperone therapy in Fabry patients. Since α-GAL is one of the best studied lysosomal storage disease, it might be used as a model to better understand other lysosomal storage diseases and as well as other diseases related to misfolded proteins, including Alzheimer's and Parkinson's diseases. Advisors/Committee Members: Scott C. Garman.

Subjects/Keywords: Pharmacological chaperones; Galactosidase; Fabry disease; Lysosomal storage diseases; Chemistry

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APA (6^th Edition):

Guce, A. I. (2010). Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones. (Doctoral Dissertation). U of Massachusetts : PhD. Retrieved from https://scholarworks.umass.edu/open_access_dissertations/202

Chicago Manual of Style (16^th Edition):

Guce, Abigail Ida. “Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones.” 2010. Doctoral Dissertation, U of Massachusetts : PhD. Accessed January 17, 2021. https://scholarworks.umass.edu/open_access_dissertations/202.

MLA Handbook (7^th Edition):

Guce, Abigail Ida. “Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones.” 2010. Web. 17 Jan 2021.

Vancouver:

Guce AI. Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones. [Internet] [Doctoral dissertation]. U of Massachusetts : PhD; 2010. [cited 2021 Jan 17]. Available from: https://scholarworks.umass.edu/open_access_dissertations/202.

Council of Science Editors:

Guce AI. Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones. [Doctoral Dissertation]. U of Massachusetts : PhD; 2010. Available from: https://scholarworks.umass.edu/open_access_dissertations/202

Universidade de Lisboa

4. Costa, Ana Carolina Ramos. Distinct strategies to overcome severe forms of PKU: The p.G46S as a model to identify small molecules modulators of protein aggregation and evaluation of an enzyme replacement approach using a nanoparticulate system.

Degree: 2017, Universidade de Lisboa

URL: https://www.rcaap.pt/detail.jsp?id=oai:repositorio.ul.pt:10451/34293

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Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2017

This work explores distinct strategies to overcome phenylketonuria (PKU; OMIM 261600), the most… (more)

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Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2017

This work explores distinct strategies to overcome phenylketonuria (PKU; OMIM 261600), the most common autosomal recessive disorder of amino acid metabolism caused by a deficiency of the hepatic human phenylalanine hydroxylase enzyme (hPAH; EC 1.14.16.1) and for which the available therapies rely mainly in a dietetic restriction. PKU is considered a conformational disease, with loss-of-function, where the normal balance between folding and degradation machineries (proteostasis) is displaced towards the accelerated degradation of the misfolded hPAH variants due to their decreased stability and high tendency to aggregate. Therefore, small molecules modulating either the conformation (pharmacological chaperones, PC) or the interaction of misfolded proteins with the cellular pathways involved in protein homeostasis (proteostasis regulators; PR) might enhance the concentration and/or location of the target proteins thus contributing to alleviate disease pathogenesis. From the more than 600 different disease-causing mutations identified to date, the hPAH p.G46S is an excellent model of aggregation-prone variants as it promotes self-association and fibril formation in vitro. Alternatively, enzyme reposition therapy (ERT) would be an universal therapeutic approach as it could rescue the full spectrum of PKU phenotypes. As such, this project aimed to: (i) hint a new class of PC, from an in-house compound library, inhibiting hPAH aggregation and using p.G46S as the study model; (ii) optimize the experimental conditions for further studies to validate PR involved in p.G46S degradation and; (iii) evaluate a potential drug delivery system, previously developed by the research group aiming to develop a ERT for PKU. By performing in vitro aggregation studies on recombinantly produced p.G46S and immunocytochemistry assays on transfected eukaryotic cells, two 3-hydroxyquinolin-2(1H)-one derivatives (C6 and C18) were identified as aggregation inhibitors. These are promising compounds to be used as scaffolds for further structure refinement. Additionally, cotransfection and co-immunoprecipitation experimental conditions were established in order to study the interactions of molecular chaperones and p.G46S, a fundamental step to further identify PR. Our assays, regarding the protective effect of chitosan-nanoparticles showed that in fact the nanoencapsulated hPAHwt presented a higher activity (after 4 h incubation in culture medium, at 37°C) than the naked protein (in the same experimental conditions). Overall, the obtained results will allow to continue to pursuit novel therapeutic strategies to PKU, which in case of the adaptation of cellular proteostasis approach, might be transversal to others conformational disorders.

Este trabalho explora diferentes estratégias para tratamento da fenilcetonúria (PKU; OMIM 261600), o erro hereditário do metabolismo dos aminoácidos mais comum, o qual é causado pela deficiência da enzima…

Advisors/Committee Members: Leandro, Ana Paula Costa dos Santos Peralta, Leandro, João Paulo Travassos.

Subjects/Keywords: Inborn errors of metabolism; Phenylketonuria; Pharmacological Chaperones; Proteostasis Regulators; Chitosan Nanoparticles; Teses de mestrado - 2017; Ciências da Saúde

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Costa, A. C. R. (2017). Distinct strategies to overcome severe forms of PKU: The p.G46S as a model to identify small molecules modulators of protein aggregation and evaluation of an enzyme replacement approach using a nanoparticulate system. (Thesis). Universidade de Lisboa. Retrieved from https://www.rcaap.pt/detail.jsp?id=oai:repositorio.ul.pt:10451/34293

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Costa, Ana Carolina Ramos. “Distinct strategies to overcome severe forms of PKU: The p.G46S as a model to identify small molecules modulators of protein aggregation and evaluation of an enzyme replacement approach using a nanoparticulate system.” 2017. Thesis, Universidade de Lisboa. Accessed January 17, 2021. https://www.rcaap.pt/detail.jsp?id=oai:repositorio.ul.pt:10451/34293.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Costa, Ana Carolina Ramos. “Distinct strategies to overcome severe forms of PKU: The p.G46S as a model to identify small molecules modulators of protein aggregation and evaluation of an enzyme replacement approach using a nanoparticulate system.” 2017. Web. 17 Jan 2021.

Vancouver:

Costa ACR. Distinct strategies to overcome severe forms of PKU: The p.G46S as a model to identify small molecules modulators of protein aggregation and evaluation of an enzyme replacement approach using a nanoparticulate system. [Internet] [Thesis]. Universidade de Lisboa; 2017. [cited 2021 Jan 17]. Available from: https://www.rcaap.pt/detail.jsp?id=oai:repositorio.ul.pt:10451/34293.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Costa ACR. Distinct strategies to overcome severe forms of PKU: The p.G46S as a model to identify small molecules modulators of protein aggregation and evaluation of an enzyme replacement approach using a nanoparticulate system. [Thesis]. Universidade de Lisboa; 2017. Available from: https://www.rcaap.pt/detail.jsp?id=oai:repositorio.ul.pt:10451/34293

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

5. Sevsek, A. Guanidinium Iminosugars as Glycosidase Inhibitors.

Degree: 2017, University Utrecht

URL: https://dspace.library.uu.nl/handle/1874/356097 ; URN:NBN:NL:UI:10-1874-356097 ; 1874/356097 ; urn:isbn:9789492679208 ; URN:NBN:NL:UI:10-1874-356097 ; https://dspace.library.uu.nl/handle/1874/356097

► Effective drug design to modulate biological processes requires knowledge of how substrates and ligands are recognized by their complementary enzymes and receptors. Glycoside trimming enzymes… (more)

▼ Effective drug design to modulate biological processes requires knowledge of how substrates and ligands are recognized by their complementary enzymes and receptors. Glycoside trimming enzymes are crucially important in a broad range of metabolic pathways, including glycoprotein and glycolipid processing and carbohydrate digestion. Thus, inhibitors of glycan-processing enzymes can be used to target an enzyme in a specific pathway to induce predictable changes in glycosylation.The outcomes of such alterations can then be studied and the information obtained is important to understand what makes an inhibitor useful in the biological process, and how inhibitors having these features can be designed in a way that can then be applied into future therapeutics.2 Lysosomal catabolic pathways involve the well-orchestrated actions of a series of enzymes for proper functioning. Lysosomal enzymes carry out precise biochemical reactions in breaking the substrates into smaller components, which need to be either recycled or excreted by the cell. Abnormal excessive accumulation of non-degraded substrates causes a variety of cellular dysfunctions that can potentially lead to a range of pathologies commonly known as lysosomal storage disorders, generally abbreviated as LSDs. Gaucher disease (GD) is the most dominant lysosomal storage disease. The condition is caused by a mutation in the glucocerebrosidase gene, which can lead to reduced activity of β-glucocerebrosidase (GBA, GBA1) the enzyme responsible for the hydrolysis of glucosylceramide (GlcCer). A deficiency in GBA activity can result in the progressive accumulation of undegraded glucosylceramide substrate leading to serious clinical symptoms and in some cases neurological complications. The primary focus for therapeutic strategies has been on reducing the cellular concentration of glycosphingolipids within the lysosome. Among the different therapeutic approaches under investigation at present, pharmacological chaperone therapy (PCT) is an interesting technique in order to restore the balance between the influx and degradation of the accumulated substrate. Pharmacological chaperones are small molecules capable of stabilizing a misfolded enzyme and thus prevent degradation by the Endoplasmic Reticulum Associated Degradation machinery (ERAD). In the case of GD, the mutant GBA enzyme is predisposed to misfolding and premature degradation in the ER but often still retains some degree of catalytic activity. An effective pharmacological chaperone-based treatment for GD would involve the pharmacologically active compound binding to and stabilize the misfolded GBA enzyme, thus facilitating its trafficking from the ER to the lysosome where it can degrade GlcCer. Certain iminosugars are highly potent and selective inhibitors of glycosidases and in some cases reversibly bind to the active site of their target enzyme in a pH-dependent manner. It may seem paradoxical to use an inhibitor to stabilize an enzyme, however, the positive outcomes of such therapeutic approaches proved to be… Advisors/Committee Members: Pieters, Roland, Martin, Nathaniel.

Subjects/Keywords: pharmacological chaperones; inhibitors of beta-glucocerebrosidase; GBA; iminosugars

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APA (6^th Edition):

Sevsek, A. (2017). Guanidinium Iminosugars as Glycosidase Inhibitors. (Doctoral Dissertation). University Utrecht. Retrieved from https://dspace.library.uu.nl/handle/1874/356097 ; URN:NBN:NL:UI:10-1874-356097 ; 1874/356097 ; urn:isbn:9789492679208 ; URN:NBN:NL:UI:10-1874-356097 ; https://dspace.library.uu.nl/handle/1874/356097

Chicago Manual of Style (16^th Edition):

Sevsek, A. “Guanidinium Iminosugars as Glycosidase Inhibitors.” 2017. Doctoral Dissertation, University Utrecht. Accessed January 17, 2021. https://dspace.library.uu.nl/handle/1874/356097 ; URN:NBN:NL:UI:10-1874-356097 ; 1874/356097 ; urn:isbn:9789492679208 ; URN:NBN:NL:UI:10-1874-356097 ; https://dspace.library.uu.nl/handle/1874/356097.

MLA Handbook (7^th Edition):

Sevsek, A. “Guanidinium Iminosugars as Glycosidase Inhibitors.” 2017. Web. 17 Jan 2021.

Vancouver:

Sevsek A. Guanidinium Iminosugars as Glycosidase Inhibitors. [Internet] [Doctoral dissertation]. University Utrecht; 2017. [cited 2021 Jan 17]. Available from: https://dspace.library.uu.nl/handle/1874/356097 ; URN:NBN:NL:UI:10-1874-356097 ; 1874/356097 ; urn:isbn:9789492679208 ; URN:NBN:NL:UI:10-1874-356097 ; https://dspace.library.uu.nl/handle/1874/356097.

Council of Science Editors:

Sevsek A. Guanidinium Iminosugars as Glycosidase Inhibitors. [Doctoral Dissertation]. University Utrecht; 2017. Available from: https://dspace.library.uu.nl/handle/1874/356097 ; URN:NBN:NL:UI:10-1874-356097 ; 1874/356097 ; urn:isbn:9789492679208 ; URN:NBN:NL:UI:10-1874-356097 ; https://dspace.library.uu.nl/handle/1874/356097

6. Decroocq, Camille. Conception et synthèse de nouvelles classes d'iminosucres d'intérêt thérapeutique : chimie click, multivalence et maladies génétiques rares : Design and synthesis of novel classes of iminosugars of therapeutic interest : click chemistry, multivalency and rare genetic diseases.

Degree: Docteur es, Chimie, 2012, Université de Strasbourg

URL: http://www.theses.fr/2012STRAF043

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Récemment, le concept de chaperon pharmacologique a émergé pour le traitement des maladies lysosomales. Comme inhibiteurs réversibles de glycosidases mutantes impliquées dans ces maladies, les… (more)

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Récemment, le concept de chaperon pharmacologique a émergé pour le traitement des maladies lysosomales. Comme inhibiteurs réversibles de glycosidases mutantes impliquées dans ces maladies, les chaperons pharmacologiques sont capables, à des concentrations sub-inhibitrices, de sauver ces enzymes des mécanismes de destruction du réticulum endoplasmique (RE). Ainsi, une partie de l’activité enzymatique est restaurée. Les iminosucres sont connus pour être une classe importante de chaperons pharmacologiques. Au cours de ce travail de thèse, de nouvelles classes d’iminosucres mono- et multivalents ont été conçues et synthétisées. Nos objectifs étaient de mettre en évidence de nouveaux chaperons pour la β-glucocérébrosidase, impliquée dans la maladie de Gaucher, mais également d’identifier de nouveaux inhibiteurs des α-glucosidases du RE impliquées dans la destruction de la protéine déficiente chez les malades atteints de la mucoviscidose. Plusieurs stratégies ont été mises en œuvre: l’utilisation d’une méthodologie de diamination d’alcènes pallado-catalysée, d’une méthodologie permettant la synthèse rapide d’une bibliothèque de composés iminosucres par chimie click ou encore de la multivalence. Une étude poussée sur la multivalence et l’inhibition de glycosidases a également été réalisée en faisant varier des paramètres clés de la multivalence tels que la valence, la charpente, le linker, ou encore la nature des ligands iminosucres. Le premier exemple d’un effet multivalent puissant jusqu’à quatre ordre de grandeur sur l’inhibition de glycosidases a été mis en évidence avec des systèmes iminosucres multivalents basés sur des charpentes de type β-cyclodextrine et fullerène C60.

Recently an innovative concept for the treatment of lysosomal diseases as emerged called pharmacological chaperone. Pharmacological chaperones are reversible inhibitors of the deficient glycosidases involved in these diseases. These molecules are able, at sub-inhibitory concentrations, to stabilize the enzymes and rescue them from the destruction by the quality control system of the endoplasmic reticulum. A part of the catalytic activity of the enzyme could be restored. Iminosugars are known to be an important class of pharmaceutical chaperones. During this PhD work, novel classes of mono- and multivalent iminosugars were designed and synthesized in order to identify novel pharmacological chaperones for the glycosidase: β-glucocerebrosidase involved in Gaucher’s disease and novel inhibitors of the α-glucosidases involved in the destruction of the defective protein delF508CFTR in cystic fibrosis. Several strategies were applied to achieve this aim. These strategies consist in the use of a synthetic methodology of palladium catalyzed alkenes diamination, the use of an efficient methodology to synthesize a library of novel iminosugars by click chemistry and the use of multivalency. A full study on the impact of multivalency on glycosidases inhibition was also completed by changing crucial structural parameters including valency, scaffold, linker and…

Advisors/Committee Members: Compain, Philippe (thesis director).

Subjects/Keywords: Iminosucres; Chaperons pharmacologiques; Inhibiteurs de glycosidases; Multivalence; Maladies lysosomales; Mucoviscidose; Cyclodextrines; Chimie click; Iminosugars; Pharmacological chaperones; Glycosidase inhibitors; Multivalency; Lysosomal diseases; Gauchers's disease; Cystic fibrosis; Click chemistry; 572.7

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Decroocq, C. (2012). Conception et synthèse de nouvelles classes d'iminosucres d'intérêt thérapeutique : chimie click, multivalence et maladies génétiques rares : Design and synthesis of novel classes of iminosugars of therapeutic interest : click chemistry, multivalency and rare genetic diseases. (Doctoral Dissertation). Université de Strasbourg. Retrieved from http://www.theses.fr/2012STRAF043

Chicago Manual of Style (16^th Edition):

Decroocq, Camille. “Conception et synthèse de nouvelles classes d'iminosucres d'intérêt thérapeutique : chimie click, multivalence et maladies génétiques rares : Design and synthesis of novel classes of iminosugars of therapeutic interest : click chemistry, multivalency and rare genetic diseases.” 2012. Doctoral Dissertation, Université de Strasbourg. Accessed January 17, 2021. http://www.theses.fr/2012STRAF043.

MLA Handbook (7^th Edition):

Decroocq, Camille. “Conception et synthèse de nouvelles classes d'iminosucres d'intérêt thérapeutique : chimie click, multivalence et maladies génétiques rares : Design and synthesis of novel classes of iminosugars of therapeutic interest : click chemistry, multivalency and rare genetic diseases.” 2012. Web. 17 Jan 2021.

Vancouver:

Decroocq C. Conception et synthèse de nouvelles classes d'iminosucres d'intérêt thérapeutique : chimie click, multivalence et maladies génétiques rares : Design and synthesis of novel classes of iminosugars of therapeutic interest : click chemistry, multivalency and rare genetic diseases. [Internet] [Doctoral dissertation]. Université de Strasbourg; 2012. [cited 2021 Jan 17]. Available from: http://www.theses.fr/2012STRAF043.

Council of Science Editors:

Decroocq C. Conception et synthèse de nouvelles classes d'iminosucres d'intérêt thérapeutique : chimie click, multivalence et maladies génétiques rares : Design and synthesis of novel classes of iminosugars of therapeutic interest : click chemistry, multivalency and rare genetic diseases. [Doctoral Dissertation]. Université de Strasbourg; 2012. Available from: http://www.theses.fr/2012STRAF043

Georgia Tech

7. Orwig, Susan D. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.

Degree: PhD, Chemistry and Biochemistry, 2011, Georgia Tech

URL: http://hdl.handle.net/1853/45816

► The inherited form of primary open angle glaucoma, a disorder characterized by increased intraocular pressure and retina degeneration, is linked to mutations in the olfactomedin… (more)

▼ The inherited form of primary open angle glaucoma, a disorder characterized by increased intraocular pressure and retina degeneration, is linked to mutations in the olfactomedin (OLF) domain of the myocilin gene. Disease-causing myocilin variants accumulate within trabecular meshwork cells instead of being secreted to the trabecular extracellular matrix thought to regulate aqueous humor flow and control intraocular pressure. Like other diseases of protein misfolding, we hypothesize myocilin toxicity originates from defects in protein biophysical properties. In this thesis, the first preparative recombinant high-yield expression and purification system for the C-terminal OLF domain of myocilin (myoc-OLF) is described. To determine the relative stability of wild-type (WT) and mutant OLF domains, a fluorescence thermal stability assay was adapted to provide the first direct evidence that mutated OLF is folded but less thermally stable than WT. In addition, mutant myocilin can be stabilized by chemical chaperones. Together, this work provides the first quantitative demonstration of compromised stability among identified OLF variants and placing myocilin glaucoma in the context of other complex diseases of protein misfolding. Subsequent investigations into the biophysical properties of WT myoc-OLF provide insight into its structure and function. In particular, myoc-OLF is stable in the presence of glycosaminoglycans (GAGs), as well as over a wide pH range in buffers with functional groups reminiscent of such GAGs. Myoc-OLF contains significant â-sheet and â-turn secondary structure as revealed by circular dichroism analysis. At neutral pH, thermal melts indicate a highly cooperative transition with a melting temperature of ~55°C. A compact core structural domain of OLF was identified by limited proteolysis and consists of approximately residues 238-461, which retains the single disulfide bond and is as stable as the full myoc-OLF construct. This construct also is capable of generating 3D crystals for structure determination. This data, presented in Chapter 3, inform new testable hypotheses for interactions with specific trabecular extracellular matrix components. To gain further insight into the biological function of myoc-OLF, a facile fluorescence chemical stability assay was designed to identify possible ligands and drug candidates. In the assay described in Chapter 4, the target protein is initially destabilized with a chemical denaturant and is tested for re-stabilization upon the addition of small molecules. The assay requires no prior knowledge of the structure and/or function of the target protein, and it is amendable to high-throughput screening. Application of the assay using a library of 1,280 compounds revealed 14 possible ligands and drug candidates for myoc-OLF that may also generate insights into myoc-OLF function. Due to the high â-sheet content of monomeric myoc-OLF and presence of an aggregated species upon myoc-OLF purification, the ability of myoc-OLF to form amyloid fibrils was suspected and… Advisors/Committee Members: Dr. Raquel Lieberman (Committee Chair), Dr. A. (Yomi) Oyelere (Committee Member), Dr. Al Merril (Committee Member), Dr. Loren Williams (Committee Member), Dr. Nicholas Hud (Committee Member), Dr. Roger Wartell (Committee Member).

Subjects/Keywords: Open-angle glaucoma; Pharmacological chaperones; High-throughput drug screen; Amyloid fibrils; Gaucher disease; Myocilin; Glaucoma; Eye Diseases; Eye Diseases Genetic aspects; Intraocular pressure; Body fluids Pressure; Eye

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Orwig, S. D. (2011). Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/45816

Chicago Manual of Style (16^th Edition):

Orwig, Susan D. “Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.” 2011. Doctoral Dissertation, Georgia Tech. Accessed January 17, 2021. http://hdl.handle.net/1853/45816.

MLA Handbook (7^th Edition):

Orwig, Susan D. “Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.” 2011. Web. 17 Jan 2021.

Vancouver:

Orwig SD. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Jan 17]. Available from: http://hdl.handle.net/1853/45816.

Council of Science Editors:

Orwig SD. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/45816

8. Stauffert, Fabien. Conception et synthèse d’iminosucres di- à tétravalents comme sondes mécanistiques et agents thérapeutiques potentiels : Design and synthesis of di- or tetravalent iminosugars as mechanistic probes and potential therapeutic agents.

Degree: Docteur es, Chimie, 2015, Université de Strasbourg

URL: http://www.theses.fr/2015STRAF061

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Dans un contexte où les iminosucres multivalents représentent, en tant qu’inhibiteurs puissants de glycosidases, des structures privilégiées pour le développement de nouveaux agents thérapeutiques, nous… (more)

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Dans un contexte où les iminosucres multivalents représentent, en tant qu’inhibiteurs puissants de glycosidases, des structures privilégiées pour le développement de nouveaux agents thérapeutiques, nous nous sommes intéressés à ce type de composés pour le traitement de deux maladies génétiques rares. Le premier axe de recherche a consisté à synthétiser des iminosucres di- à tétravalents en série 1-désoxymannojirimycine dans le but d’inhiber l’α1,2-mannosidase I du réticulum endoplasmique qui est impliquée dans la destruction de la protéine delF508-CFTR chez les malades atteints de la mucoviscidose. Un effet multivalent fort sur la correction de cette protéine mutée a alors été mis en évidence avec un composé trivalent basé sur le pentaérythritol. Efficace à des concentrations submicromolaires, ce dernier s’est montré 140 fois plus efficace que le modèle monovalent correspondant. Le second axe de recherche a consisté à identifier de nouveaux chaperons pharmacologiques de la β-glucocérébrosidase, l’enzyme lysosomale impliquée dans la maladie de Gaucher. Pour cela, nous avons préparé une série d’iminosucres hétérodivalents conçus pour cibler simultanément le site actif et un site secondaire de cette enzyme. Même si cet objectif n’a pas encore été atteint, nous avons malgré tout mis en évidence des chaperons monovalents capables de quasiment quadrupler l’activité de la β-glucocérébrosidase portant la mutation G202R. En marge de ces deux axes principaux, une sonde mécanistique basée sur un C-glycoside multivalent a également été développée dans le but de préciser les mécanismes à l’origine des effets multivalents puissants observés pour l’inhibition des glycosidases.

Because multivalent iminosugars represent, as potent glycosidase inhibitors, privileged structures for the design of novel drugs, we took a particular interest in this class of compounds for the treatment of two rare genetic diseases. The first research topic was dedicated to the synthesis of di- to tetravalent iminosugars in the 1-deoxymannojirimycin series in order to inhibit the endoplasmic reticulum α1,2-mannosidase I involved in the destruction of delF508-CFTR, the mutant protein responsible of cystic fibrosis. A strong multivalent effect for restoring its activity in cells was reported with a trivalent analogue based on pentaerythritol. This submicromolar corrector was found to be 140-fold more potent than the corresponding monovalent model. The second research topic focused on the identification of novel pharmacological chaperones of the β-glucocerebrosidase, the lysosomal enzyme involved in Gaucher’s disease. For this purpose, we developed a series of heterodivalent iminosugars designed to both bind to the active site and a secondary site of the enzyme. This goal could not be reached yet, nevertheless we identified monovalent chaperones which were able to fourfold increase β-glucocerebrosidase activity in G202R cell lines. Next to these main research topics, a mechanistic probe based on a multivalent C-glycoside was also developed to investigate…

Advisors/Committee Members: Compain, Philippe (thesis director).

Subjects/Keywords: Iminosucres; Multivalence; Inhibiteurs de glycosidase; Mucoviscidose; Protéine CFTR; Correcteur; Maladie de Gaucher; Β-Glucocérébrosidase; Chaperons pharmacologiques; Chimie click; C-Glycoside; Iminosugars; Multivalency; Glycosidase inhibitors; Cystic fibrosis; CFTR corrector; Gaucher’s disease; Β-Glucocerebrosidase; Pharmacological chaperones; C-Glycoside; Click chemistry; 547.2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Stauffert, F. (2015). Conception et synthèse d’iminosucres di- à tétravalents comme sondes mécanistiques et agents thérapeutiques potentiels : Design and synthesis of di- or tetravalent iminosugars as mechanistic probes and potential therapeutic agents. (Doctoral Dissertation). Université de Strasbourg. Retrieved from http://www.theses.fr/2015STRAF061

Chicago Manual of Style (16^th Edition):

Stauffert, Fabien. “Conception et synthèse d’iminosucres di- à tétravalents comme sondes mécanistiques et agents thérapeutiques potentiels : Design and synthesis of di- or tetravalent iminosugars as mechanistic probes and potential therapeutic agents.” 2015. Doctoral Dissertation, Université de Strasbourg. Accessed January 17, 2021. http://www.theses.fr/2015STRAF061.

MLA Handbook (7^th Edition):

Stauffert, Fabien. “Conception et synthèse d’iminosucres di- à tétravalents comme sondes mécanistiques et agents thérapeutiques potentiels : Design and synthesis of di- or tetravalent iminosugars as mechanistic probes and potential therapeutic agents.” 2015. Web. 17 Jan 2021.

Vancouver:

Stauffert F. Conception et synthèse d’iminosucres di- à tétravalents comme sondes mécanistiques et agents thérapeutiques potentiels : Design and synthesis of di- or tetravalent iminosugars as mechanistic probes and potential therapeutic agents. [Internet] [Doctoral dissertation]. Université de Strasbourg; 2015. [cited 2021 Jan 17]. Available from: http://www.theses.fr/2015STRAF061.

Council of Science Editors:

Stauffert F. Conception et synthèse d’iminosucres di- à tétravalents comme sondes mécanistiques et agents thérapeutiques potentiels : Design and synthesis of di- or tetravalent iminosugars as mechanistic probes and potential therapeutic agents. [Doctoral Dissertation]. Université de Strasbourg; 2015. Available from: http://www.theses.fr/2015STRAF061

9. Makley, Leah Nicole. Chemical Approaches for ‘Undruggable’ Targets: The Discovery of Ligands for Small Heat Shock Proteins.

Degree: PhD, Medicinal Chemistry, 2014, University of Michigan

URL: http://hdl.handle.net/2027.42/109032

► Small heat shock proteins (sHSPs) are molecular chaperones that protect against protein aggregation in response to stress. These chaperones have been linked to a number… (more)

▼ Small heat shock proteins (sHSPs) are molecular chaperones that protect against protein aggregation in response to stress. These chaperones have been linked to a number of protein misfolding diseases, including neurodegenerative disorders and cataracts. However, sHSPs are considered “undruggable” because they lack enzymatic activity or obvious ligand-binding sites. Thus, sHSPs are emblematic of potential drug targets emerging from large-scale genetic efforts. They are clearly linked to disease, yet it is not clear how to develop drug-small molecules to act on this knowledge. In this thesis work, I employed a number of high throughput biophysical approaches to discover cryptic binding sites on two sHSPs: Hsp27 and alphaB-crystallin (cryAB). Using a multifaceted approach involving computational approaches, differential scanning fluorimetry, fragment-based NMR screening and rational design, three unanticipated binding sites were discovered. Medicinal chemistry and structural efforts yielded four classes of small molecules, with representatives that bind each of the three cryptic pockets. One of these chemical series was developed as a potential new therapeutic for the topical treatment of cataract. These molecules bind the native dimer of cryAB and promote its chaperone functions, reversing cataracts in mouse and human lens models. Another series binds to a region of Hsp27 that is important for its interactions with the Hsp70 class of chaperones, showing promise as a chemical probe for understanding how chaperones regulate protein homeostasis. This thesis work has significantly advanced our knowledge of sHSP ‘druggability’ and revealed at least three binding sites for further development. Moreover, these efforts represent a detailed, head-to-head comparison of modern HTS methods to discover ligands for cryptic binding sites. The strengths and weaknesses of these approaches are important in designing screening campaigns for other ‘undruggable’ targets emerging from genetic studies. Advisors/Committee Members: Gestwicki, Jason E. (committee member), Carlson, Heather A. (committee member), Ruotolo, Brandon Thomas (committee member), Showalter, Hollis D. (committee member), Cierpicki, Tomasz (committee member).

Subjects/Keywords: Drug Discovery; Medicinal Chemistry; Undruggable Targets; Small Heat Shock Proteins; Pharmacological Chaperones; Protein Misfolding; Chemistry; Science

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10 more images…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Makley, L. N. (2014). Chemical Approaches for ‘Undruggable’ Targets: The Discovery of Ligands for Small Heat Shock Proteins. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/109032

Chicago Manual of Style (16^th Edition):

Makley, Leah Nicole. “Chemical Approaches for ‘Undruggable’ Targets: The Discovery of Ligands for Small Heat Shock Proteins.” 2014. Doctoral Dissertation, University of Michigan. Accessed January 17, 2021. http://hdl.handle.net/2027.42/109032.

MLA Handbook (7^th Edition):

Makley, Leah Nicole. “Chemical Approaches for ‘Undruggable’ Targets: The Discovery of Ligands for Small Heat Shock Proteins.” 2014. Web. 17 Jan 2021.

Vancouver:

Makley LN. Chemical Approaches for ‘Undruggable’ Targets: The Discovery of Ligands for Small Heat Shock Proteins. [Internet] [Doctoral dissertation]. University of Michigan; 2014. [cited 2021 Jan 17]. Available from: http://hdl.handle.net/2027.42/109032.

Council of Science Editors:

Makley LN. Chemical Approaches for ‘Undruggable’ Targets: The Discovery of Ligands for Small Heat Shock Proteins. [Doctoral Dissertation]. University of Michigan; 2014. Available from: http://hdl.handle.net/2027.42/109032

University of Oulu

10. Hakalahti, A. (Anna). Human β₁-adrenergic receptor:biosynthesis, processing and the carboxyl-terminal polymorphism.

Degree: 2011, University of Oulu

URL: http://urn.fi/urn:isbn:9789514295263

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Abstract The β1-adrenergic receptor (β1AR) belongs to the large family of G protein-coupled receptors. It is activated by epinephrine and norepinephrine and thus has a… (more)

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Abstract The β1-adrenergic receptor (β1AR) belongs to the large family of G protein-coupled receptors. It is activated by epinephrine and norepinephrine and thus has a central role in mediating the effects of the sympathetic nervous system. β1AR is the predominant adrenergic receptor in the heart, where it mediates positive inotropy and chronotropy. Thus, it is the most important target receptor for β-adrenergic antagonists, which are widely used in the treatment of cardiovascular diseases. Furthermore, β1AR is also expressed in the brain, where it has a crucial role in regulating memory formation and synaptic plasticity. Human β1AR (hβ1AR) has two polymorphisms, one at each terminus. The carboxyl-terminal (C-terminal) Arg389Gly8.56 polymorphism has previously been shown to have functional significance. Despite the clinical importance of hβ1AR, its biosynthetic profile and post-translational processing have not been well characterized to date. The aims of the present study were to shed light on these events, focusing on the limited proteolysis of hβ1AR and the impact of β-adrenergic ligands on receptor processing. In addition, the C-terminal polymorphism and its associations with certain parameters were investigated in a population consisting of survivors of acute myocardial infarction (AMI). By using a heterologous expression system, hβ1AR biosynthesis was revealed to be efficient and rapid. The N-terminus of the mature receptor was modified with O-glycans and one N-glycan, but despite these modifications it was subject to cleavage at the cell surface that resulted in two C-terminal fragments. The cleavage was mediated by a metalloproteinase, and importantly, it also occurred in vivo. Moreover, receptor activation enhanced the cleavage, which suggests that it represents a novel regulatory mechanism of hβ1AR. Interestingly, those ligands that enhanced the cleavage stabilized intracellular hβ1AR precursors, possibly via a pharmacological chaperone activity. Thus, the present study demonstrates that β-adrenergic ligands can have different regulatory effects on distinct hβ1AR forms. Among the AMI survivors, the Arg3898.56 homozygotes had significantly increased left ventricular mass indexes, when compared to the Gly3898.56 carriers, which suggests an association between Arg3898.56 and left ventricular hypertrophy (LVH). When euglycemic and diabetic patients were analyzed separately, the association existed among the euglycemic patients but was not present in diabetic patients. Diabetes is one of several risk factors that have previously been shown to influence the progression of LVH. Here, diabetes was shown to have a stronger effect on the development of LVH, when compared with the Arg3898.56 variant of hβ1AR.

Tiivistelmä β1-adrenerginen reseptori (β1AR) kuuluu laajaan G-proteiineihin kytkettyjen reseptorien perheeseen. β1AR on tärkeässä asemassa sympaattisen hermoston toiminnassa. Sydämessä β1AR on vallitseva adrenerginen reseptori, ja sydänlihaksen supistusvireys sekä -taajuus voimistuvat β1AR:n aktivaation…

Advisors/Committee Members: Petäjä-Repo, U. (Ulla).

Subjects/Keywords: G-protein-coupled receptors; biosynthesis; down-regulation; glycosylation; left ventricular hypertrophy; limited proteolysis; metalloproteinases; myocardial infarction; pharmacological chaperones; single nucleotide polymorphism; up-regulation; β-adrenergic antagonist; β<; sub>; 1<; /sub>; -adrenergic receptor; G-proteiiniin kytketyt reseptorit; biosynteesi; farmakologiset kaperonit; glykosylaatio; metalloproteinaasit; rajoitettu proteolyysi; sydäninfarkti; vaimennussäätely; vasemman kammion hypertrofia; yksittäisen nukleotidin polymorfia; ylössäätely; β-adrenerginen antagonisti

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hakalahti, A. (. (2011). Human β₁-adrenergic receptor:biosynthesis, processing and the carboxyl-terminal polymorphism. (Doctoral Dissertation). University of Oulu. Retrieved from http://urn.fi/urn:isbn:9789514295263

Chicago Manual of Style (16^th Edition):

Hakalahti, A (Anna). “Human β₁-adrenergic receptor:biosynthesis, processing and the carboxyl-terminal polymorphism.” 2011. Doctoral Dissertation, University of Oulu. Accessed January 17, 2021. http://urn.fi/urn:isbn:9789514295263.

MLA Handbook (7^th Edition):

Hakalahti, A (Anna). “Human β₁-adrenergic receptor:biosynthesis, processing and the carboxyl-terminal polymorphism.” 2011. Web. 17 Jan 2021.

Vancouver:

Hakalahti A(. Human β₁-adrenergic receptor:biosynthesis, processing and the carboxyl-terminal polymorphism. [Internet] [Doctoral dissertation]. University of Oulu; 2011. [cited 2021 Jan 17]. Available from: http://urn.fi/urn:isbn:9789514295263.

Council of Science Editors:

Hakalahti A(. Human β₁-adrenergic receptor:biosynthesis, processing and the carboxyl-terminal polymorphism. [Doctoral Dissertation]. University of Oulu; 2011. Available from: http://urn.fi/urn:isbn:9789514295263

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