scholarly journals Binding of 3,4,5,6-Tetrahydroxyazepanes to the Acid-β-glucosidase Active Site: Implications for Pharmacological Chaperone Design for Gaucher Disease

Biochemistry ◽  
2011 ◽  
Vol 50 (49) ◽  
pp. 10647-10657 ◽  
Author(s):  
Susan D. Orwig ◽  
Yun Lei Tan ◽  
Neil P. Grimster ◽  
Zhanqian Yu ◽  
Evan T. Powers ◽  
...  
Keyword(s):  
Active Site ◽  
Gaucher Disease ◽  
Pharmacological Chaperone

N-Glycosylation and Gaucher Disease Mutation Allosterically Alter Active-Site Dynamics of Acid-β-Glucosidase

ACS Catalysis ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 1810-1820 ◽  
Author(s):  
Michael Gregory Souffrant ◽  
Xin-Qiu Yao ◽  
Mohamed Momin ◽  
Donald Hamelberg
Keyword(s):  
Active Site ◽  
Gaucher Disease ◽  
Disease Mutation

In silicoanalyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay–Sachs disease

2017 ◽  
Vol 15 (44) ◽  
pp. 9297-9304 ◽  
Author(s):  
Atsushi Kato ◽  
Izumi Nakagome ◽  
Shinpei Nakagawa ◽  
Kyoko Kinami ◽  
Isao Adachi ◽  
...  
Keyword(s):  
Active Site ◽  
Wild Type ◽  
Pharmacological Chaperone ◽  
Tay Sachs Disease

DMDP amide restored Hex A activity in the G269S Tay–Sachs patient cells up to 43% of the wild type.

Conformationally-LockedN-Glycosides with Selective β-Glucosidase Inhibitory Activity: Identification of a New Non-Iminosugar-Type Pharmacological Chaperone for Gaucher Disease

2012 ◽  
Vol 55 (15) ◽  
pp. 6857-6865 ◽  
Author(s):  
Javier Castilla ◽  
Rocío Rísquez ◽  
Deysi Cruz ◽  
Katsumi Higaki ◽  
Eiji Nanba ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Gaucher Disease ◽  
Pharmacological Chaperone

A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity

2008 ◽  
Vol 389 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Jian-Qiang Fan
Keyword(s):  
Enzyme Activity ◽  
Active Site ◽  
Protein Misfolding ◽  
Enzyme Inhibitors ◽  
Lysosomal Storage ◽  
New Paradigm ◽  
Inherited Disorders ◽  
Pharmacological Chaperone ◽  
Mutant Proteins ◽  
Enzyme Active Site

Abstract Pharmacological chaperone therapy is an emerging counterintuitive approach to treat protein deficiencies resulting from mutations causing misfolded protein conformations. Active-site-specific chaperones (ASSCs) are enzyme active-site directed small molecule pharmacological chaperones that act as a folding template to assist protein folding of mutant proteins in the endoplasmic reticulum (ER). As a result, excessive degradation of mutant proteins in the ER-associated degradation (ERAD) machinery can be prevented, thus restoring enzyme activity. Lysosomal storage disorders (LSDs) are suitable candidates for ASSC treatment, as the levels of enzyme activity needed to prevent substrate storage are relatively low. In addition, ASSCs are orally active small molecules and have potential to gain access to most cell types to treat neuronopathic LSDs. Competitive enzyme inhibitors are effective ASSCs when they are used at sub-inhibitory concentrations. This whole new paradigm provides excellent opportunity for identifying specific drugs to treat a broad range of inherited disorders. This review describes protein misfolding as a pathophysiological cause in LSDs and provides an overview of recent advances in the development of pharmacological chaperone therapy for the diseases. In addition, a generalized guidance for the design and screening of ASSCs is also presented.

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.

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.

scholarly journals Structural basis of pharmacological chaperoning for human β-galactosidase

2014 ◽  
Vol 70 (a1) ◽  
pp. C843-C843
Author(s):  
Hironori Suzuki ◽  
Umeharu Ohto ◽  
Katsumi Higaki ◽  
Teresa Mena-Barragán ◽  
Matilde Aguilar-Moncayo ◽  
...  
Keyword(s):  
Active Site ◽  
Neurodegenerative Disorder ◽  
Lysosomal Storage Diseases ◽  
Japanese Patients ◽  
Structural Basis ◽  
Lysosomal Storage ◽  
Active Site Residues ◽  
Recognition Mechanism ◽  
Gm1 Gangliosidosis ◽  
Pharmacological Chaperone

GM1-gangliosidosis and Morquio B are rare lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme human β-Galactosidase (β-Gal), frequently related to misfolding and subsequent endoplasmic reticulum-associated degradation (ERAD) due to mutations in the β-Gal gene. Pharmacological chaperone (PC) therapy is a newly developed molecular therapeutic approach by using small molecule ligands of the mutant enzyme that are able to promote the correct folding, prevent ERAD and promote trafficking to the lysosome. Here, we present the enzymological properties of wild-type human β-Gal and two representative mutations in GM1 gangliosidosis Japanese patients (R201C and I51T). We have also evaluated the PC effect of two competitive inhibitors of β-Gal. Moreover, we determined the crystal structures of β-Gal in complex with these compouds and two structurally related analogues to elucidate the detailed atomic view of the recognition mechanism. All compounds bind to the active site of β-Gal with the sugar moiety making hydrogen bonds to active site residues. Moreover, the binding affinity, the enzyme selectivity and the PC potential are strongly affected by the mono or bicyclic structure of the core as well as the orientation, the nature and the length of the exocyclic substituent. These results provide understanding on the mechanism of action of β-Gal selective chaperoning by newly developed PC compounds.

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