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BioAssay: AID 1473

Quantitative High-Throughput Screen for Inhibitors and Activators of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Disease: Summary

Alpha-glucosidase is responsible for hydrolysis of terminal, non-reducing 1,4-linked alpha-D-glucose residues with release of alpha-D-glucose. It is a lysosomal hydrolase that is required for the degradation of a small percentage (1-3%) of cellular glycogen in human. Deficiency of this enzyme results in glycogen-storage disease type II (GSDII), also referred to as Pompe disease, an autosomal more ..
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 Tested Compounds
 Tested Compounds
All(5)
 
 
Probe(1)
 
 
Active(1)
 
 
Inactive(1)
 
 
Inconclusive(3)
 
 
 Tested Substances
 Tested Substances
All(5)
 
 
Probe(1)
 
 
Active(1)
 
 
Inactive(1)
 
 
Inconclusive(3)
 
 
AID: 1473
Data Source: NCGC (AGLU005)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-01-02
Modify Date: 2010-01-22

Data Table ( Complete ):           Active    All
Target
BioActive Compound: Chemical Probe: 1    Active: 1
Depositor Specified Assays
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AIDNameTypeComment
1466qHTS Assay for Inhibitors of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Diseaseconfirmatory
2242qHTS Assay for Activators of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Diseaseconfirmatory
2112qHTS Assay for Inhibitors and Activators of Human alpha-Glucosidase From Spleen Homogenateconfirmatory
2100qHTS Assay for Inhibitors and Activators of Human alpha-Glucosidase Cleavage of Glycogenconfirmatory
2113Confirmation of Inhibitors and Activators of Human alpha-Glucosidase From Spleen Homogenateconfirmatory
2115Confirmation of Inhibitors and Activators of Purified Human alpha-Glucosidaseconfirmatory
2111Confirmation of Inhibitors and Activators of Human alpha-Glucosidase From Spleen Homogenate Using an Alternate Red Fluorescent Susbtrateconfirmatory
2110Confirmation of Inhibitors and Activators of Purified Human alpha-Glucosidase Using an Alternate Red Fluorescent Susbtrateconfirmatory
2108Confirmation of Inhibitors of Human alpha-Galactosidase Using Spleen Homogenateconfirmatory
2109Confirmation of Inhibitors and Activators of Purified Human alpha-Galactosidaseconfirmatory
2107qHTS Assay for Inhibitors and Activators of Human alpha-Galactosidase From Spleen Homogenateconfirmatory
2101qHTS Assay for Inhibitors and Activators of N370S glucocerebrosidase as a Potential Chaperone Treatment of Gaucher Diseaseconfirmatory
1467qHTS Assay for Inhibitors of Human alpha-Galactosidase at pH 4.5.confirmatory
2293Direct Measure of the Activation of Acid alpha-Glucosidase Catalytic Rateother
2641qHTS Assay for Inhibitors of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Disease: Stabilizers of Alpha-Glucosidase Under Thermal Denaturation Conditionsother
504681Inhibitors of Human alpha-Glucosidase: PBS Stability Profilingother
504686Inhibitors of Human alpha-Glucosidase: Caco-2 Cell Permeability Profilingother
504688Inhibitors of Human alpha-Glucosidase: Caco-2 Efflux Ratio Profilingother
540341Activators of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Disease: Glucocerebrosidase Counter Screenconfirmatory
540361Activators of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Disease: Alpha-Galactosidase Counter Screenconfirmatory
602122qHTS for Activators of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Disease: Fibroblast Translocationother
602237qHTS for Activators of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Disease: Aqueous Solubilityother
602238qHTS for Activators of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Disease: Metabolic Stabilityother
602239qHTS for Activators of Human alpha-Glucosidase as a Potential Chaperone Treatment of Pompe Disease: Metabolic Stability in presence of NADPHother
Description:
NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Production centers Network [MLPCN]

MLPCN Grant: 1R03MH084841-01
Assay Submitter (PI): Wei Zheng

NCGC Assay Overview:

Alpha-glucosidase is responsible for hydrolysis of terminal, non-reducing 1,4-linked alpha-D-glucose residues with release of alpha-D-glucose. It is a lysosomal hydrolase that is required for the degradation of a small percentage (1-3%) of cellular glycogen in human. Deficiency of this enzyme results in glycogen-storage disease type II (GSDII), also referred to as Pompe disease, an autosomal recessive disorder. Structurally normal glycogen is accumulated in lysosomes and cytoplasm in affected patients, primarily in muscle tissues. Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and leads to cellular injury. In turn, this leads to enlargement and dysfunction of the entire organ involved (eg, cardiomyopathy and muscle weakness).

It has reported that the improper folding and trafficking of alpha-glucosidase resulting from the genetic mutations may account for a significant number of Pompe patients. N-butyl-deoxynojirimycin, an inhibitor of alpha-glucosidase, was reported to exhibit the pharmacological chaperone activity, which significantly increases the mutant enzyme activity in cells. We optimized this alpha-glucosidase assay in 1536-well plate format for identifying the novel small molecule inhibitors with the structures other than the sugar analogs in order to develop the new pharmacological chaperones.

The probe is an activator of alpha-Glucosidase in purified in vitro assays, as well as tissue homogenate assays. This compound may be useful as a chemical chaperone of alpha-Glucosidase, though this has not yet been demonstrated for this compound.
Protocol
Please refer to other AIDs (1466, 2242, 2112, 2100, 2113, 2115, 2111, 2110, 2108, 2109, 2107, 2101) for detailed assay protocols.
Comment
This summary is written for the purposes of summarizing the probe activities from the project. MLSCN probes are given a score of 100. Molecules in the prior art are given a score of 80. Other, less active molecules in the same chemical series as the probe molecules are given a score of 50. Molecules pending validation are given a score of 10. Inactive analogues from these series are given a score of 0.
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1Activity Summary Nature of interaction of the sample with the enzyme.String
2alpha-Glucosidase Potency (Purified; Red Substrate)The concentration of sample yielding half-maximal sample efficacy.FloatμM
3alpha-Glucosidase Potency (Tissue homogenate; Red Substrate)The concentration of sample yielding half-maximal sample efficacy.FloatμM
4beta-Glucosidase ActivityNature of interaction of the sample with the enzyme.String
5alpha-Galactosidase ActivityNature of interaction of the sample with the enzyme.String
6alpha-Glucosidase Activity (Purified; Glycogen)Nature of interaction of the sample with the enzyme.String
Additional Information
Grant Number: 1R03MH084841-01

Data Table (Concise)
Classification
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