scholarly journals Azasugar inhibitors as pharmacological chaperones for Krabbe disease

2015 ◽  
Vol 6 (5) ◽  
pp. 3075-3086 ◽  
Author(s):  
Chris H. Hill ◽  
Agnete H. Viuff ◽  
Samantha J. Spratley ◽  
Stéphane Salamone ◽  
Stig H. Christensen ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Krabbe Disease ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones

Modified azasugar molecules have been synthesized and characterized as excellent pharmacological chaperone candidates to treat the neurodegenerative disorder Krabbe disease.

scholarly journals Low Psychosine in Krabbe Disease with Onset in Late Infancy: A Case Report

2021 ◽  
Vol 7 (2) ◽  
pp. 28
Author(s):  
Camille S. Corre ◽  
Dietrich Matern ◽  
Joan E. Pellegrino ◽  
Carlos A. Saavedra-Matiz ◽  
Joseph J. Orsini ◽  
...  
Keyword(s):  
New York ◽  
Enzyme Activity ◽  
Clinical Presentation ◽  
Neurodegenerative Disorder ◽  
New York State ◽  
Disease Onset ◽  
Early Infancy ◽  
Krabbe Disease ◽  
Activity Levels ◽  
Hematopoietic Stem

Krabbe disease (KD) is a rare inherited neurodegenerative disorder caused by a deficiency in galactocerebrosidase enzyme activity, which can present in early infancy, requiring an urgent referral for hematopoietic stem cell transplantation, or later in life. Newborn screening (NBS) for KD requires identification and risk-stratification of patients based on laboratory values to predict disease onset in early infancy or later in life. The biomarker psychosine plays a key role in NBS algorithms to ascertain probability of early-onset disease. This report describes a patient who was screened positive for KD in New York State, had a likely pathogenic genotype, and showed markedly reduced enzyme activity but surprisingly low psychosine levels. The patient ultimately developed KD in late infancy, an outcome not clearly predicted by existing NBS algorithms. It remains critical that psychosine levels be evaluated alongside genotype, enzyme activity levels, and the patient’s evolving clinical presentation, ideally in consultation with experts in KD, in order to guide diagnosis and plans for monitoring.

Pharmacological chaperone therapeutics for Krabbe disease

2019 ◽  
Vol 126 (2) ◽  
pp. S92
Author(s):  
Chris W. Lee ◽  
Arulmani Manavalan ◽  
Dana Clausen
Keyword(s):  
Krabbe Disease ◽  
Pharmacological Chaperone

scholarly journals Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy

2021 ◽  
Author(s):  
Christopher Hatton ◽  
Simona S. Ghanem ◽  
David Koss ◽  
Ilham Yahya Abdi ◽  
Elizabeth Gibbons ◽  
...  
Keyword(s):  
Lewy Body ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Krabbe Disease ◽  
Biological Processes ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Galc Gene ◽  
The Brain ◽  
Lewy Body Diseases

Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to α-synuclein localisation and expression of modifications associated with LBD. To determine whether α-synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of α-synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.

scholarly journals Distinct proteostasis states drive pharmacologic chaperone susceptibility for Cystic Fibrosis Transmembrane Conductance Regulator misfolding mutants

2021 ◽  
Author(s):  
Eli Fritz McDonald ◽  
Carleen Mae P. Sabusap ◽  
Minsoo Kim ◽  
Lars Plate
Keyword(s):  
Cystic Fibrosis ◽  
Protein Misfolding ◽  
Clinical Success ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones ◽  
Misfolding Diseases ◽  
The Impact ◽  
Cystic Fibrosis Transmembrane

ABSTRACTPharmacological chaperones represent a class of therapeutic compounds for treating protein misfolding diseases. One of the most prominent examples is the FDA-approved pharmacological chaperone lumacaftor (VX-809), which has transformed cystic fibrosis (CF) therapy. CF is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). VX-809 corrects folding of F508del CFTR, the most common patient mutation, yet F508del exhibits only mild VX-809 response. In contrast, rarer mutations P67L and L206W are hyper-responsive to VX-809, while G85E is non-responsive. Despite the clinical success of VX-809, the mechanistic origin for the distinct susceptibility of mutants remains unclear. Here, we use interactomics to characterize the impact of VX-809 on proteostasis interactions of P67L and L206W and compare these to F508del and G85E. We determine hyper-responsive mutations P67L and L206W exhibit decreased interactions with proteasomal, and autophagy degradation machinery compared to F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response, and inhibiting the lysosome attenuates F508del VX-809 response. Our data suggests a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.

scholarly journals Second-Generation Pharmacological Chaperones: Beyond Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3145 ◽  
Author(s):  
My Lan Tran ◽  
Yves Génisson ◽  
Stéphanie Ballereau ◽  
Cécile Dehoux
Keyword(s):  
Protein Misfolding ◽  
First Generation ◽  
Second Generation ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Pharmacological Chaperone ◽  
Conformational Diseases ◽  
Pharmacological Chaperones ◽  
Drug Candidates ◽  
Binding Pockets

Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.

scholarly journals Design of a New α-1-C-Alkyl-DAB Derivative Acting as a Pharmacological Chaperone for β-Glucocerebrosidase Using Ligand Docking and Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2683 ◽  
Author(s):  
Izumi Nakagome ◽  
Atsushi Kato ◽  
Noriyuki Yamaotsu ◽  
Tomoki Yoshida ◽  
Shin-ichiro Ozawa ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Binding Affinity ◽  
Gaucher Disease ◽  
Point Mutations ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones ◽  
Dynamics Simulations

Some point mutations in β-glucocerebrosidase cause either improper folding or instability of this protein, resulting in Gaucher disease. Pharmacological chaperones bind to the mutant enzyme and stabilize this enzyme; thus, pharmacological chaperone therapy was proposed as a potential treatment for Gaucher disease. The binding affinities of α-1-C-alkyl 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives, which act as pharmacological chaperones for β-glucocerebrosidase, abruptly increased upon elongation of their alkyl chain. In this study, the primary causes of such an increase in binding affinity were analyzed using protein–ligand docking and molecular dynamics simulations. We found that the activity cliff between α-1-C-heptyl-DAB and α-1-C-octyl-DAB was due to the shape and size of the hydrophobic binding site accommodating the alkyl chains, and that the interaction with this hydrophobic site controlled the binding affinity of the ligands well. Furthermore, based on the aromatic/hydrophobic properties of the binding site, a 7-(tetralin-2-yl)-heptyl-DAB compound was designed and synthesized. This compound had significantly enhanced activity. The design strategy in consideration of aromatic interactions in the hydrophobic pocket was useful for generating effective pharmacological chaperones for the treatment of Gaucher disease.

Functional Rescue of the Constitutively Internalized V2 Vasopressin Receptor Mutant R137H by the Pharmacological Chaperone Action of SR49059

2004 ◽  
Vol 18 (8) ◽  
pp. 2074-2084 ◽  
Author(s):  
Virginie Bernier ◽  
Monique Lagacé ◽  
Michèle Lonergan ◽  
Marie-Françoise Arthus ◽  
Daniel G. Bichet ◽  
...  
Keyword(s):  
Cell Surface ◽  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Vasopressin Receptor ◽  
Metabolic Labeling ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones ◽  
Receptor Mutant ◽  
V2 Vasopressin Receptor ◽  
And Function

Abstract In most cases, nephrogenic diabetes insipidus results from mutations in the V2 vasopressin receptor (V2R) gene that cause intracellular retention of improperly folded receptors. We previously reported that cell permeable V2R antagonists act as pharmacological chaperones that rescue folding, trafficking, and function of several V2R mutants. More recently, the vasopressin antagonist, SR49059, was found to be therapeutically active in nephrogenic diabetes insipidus patients. Three of the patients with positive responses harbored the mutation R137H, previously reported to lead to constitutive endocytosis. This raises the possibility that, instead of acting as a pharmacological chaperone by favoring proper maturation of the receptors, SR49059 could mediate its action on R137H V2R by preventing its endocytosis. Here we report that the β-arrestin-mediated constitutive endocytosis of R137H V2R is not affected by SR49059, indicating that the functional rescue observed does not result from a stabilization of the receptor at the cell surface. Moreover, metabolic labeling revealed that R137H V2R is also poorly processed to the mature form. SR49059 treatment significantly improved its maturation and cell surface targeting, indicating that the functional rescue of R137H V2Rs results from the pharmacological chaperone action of the antagonist.

scholarly journals The mechanism of sphingolipid processing revealed by a GALC-SapA complex structure

2017 ◽  
Author(s):  
Chris H. Hill ◽  
Georgia M. Cook ◽  
Samantha J. Spratley ◽  
Stephen C. Graham ◽  
Janet E. Deane
Keyword(s):  
Active Site ◽  
Open Channel ◽  
Neurodegenerative Disorder ◽  
Complex Structure ◽  
Hydrolytic Enzymes ◽  
Lipid Binding ◽  
Krabbe Disease ◽  
Enzyme Active Site ◽  
Hydrophobic Cavity ◽  
Essential Components

AbstractSphingolipids are essential components of cellular membranes and defects in their synthesis or degradation cause severe human diseases. The efficient degradation of sphingolipids in the lysosome requires lipid-binding saposin proteins and hydrolytic enzymes. The glycosphingolipid galactocerebroside is the primary lipid component of the myelin sheath and is degraded by the hydrolase β-galactocerebrosidase (GALC). This enzyme requires the saposin SapA for lipid processing and defects in either of these proteins causes a severe neurodegenerative disorder, Krabbe disease. Here we present the structure of a glycosphingolipid-processing complex, revealing how SapA and GALC form a heterotetramer with an open channel connecting the enzyme active site to the SapA hydrophobic cavity. This structure defines how a soluble hydrolase can cleave the polar glycosyl headgroups of these essential lipids from their hydrophobic ceramide tails. Furthermore, the molecular details of this interaction reveal how specificity of saposin binding to hydrolases is encoded.

Synthesis and biological evaluation of d-gluconhydroximo-1,5-lactam and its oxime-substituted derivatives as pharmacological chaperones for the treatment of Gaucher disease

MedChemComm ◽  
2016 ◽  
Vol 7 (2) ◽  
pp. 365-370 ◽  
Author(s):  
Jiajia Wang ◽  
Xiaomin Wang ◽  
Yunyan Zhao ◽  
Xiaoyao Ma ◽  
Yue Wan ◽  
...  
Keyword(s):  
Cell Line ◽  
Gaucher Disease ◽  
Biological Evaluation ◽  
Mutant Protein ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones ◽  
Related Cell ◽  
Synthesis And Biological Evaluation

38 was an efficient pharmacological chaperone for GCase-related cell line N370S, which can effectively promote the activity of the mutant protein by 1.93-fold at 12.5 μM.

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