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 ..
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.
Please refer to other AIDs (1466, 2242, 2112, 2100, 2113, 2115, 2111, 2110, 2108, 2109, 2107, 2101) for detailed assay protocols.
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.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 2
MLP Probe ML# for probe 1: ML201
PubChem Substance ID (SID) for probe 1: 89650104
PubChem Compound ID (CID) for probe 1: 20969430
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK153219/ (ID: 3046350)
Grant number for probe 1: MH084841-01
MLP Probe ML# for probe 2: ML247
PubChem Substance ID (SID) for probe 2: 85267344
PubChem Compound ID (CID) for probe 2: 44246403
Probe type for probe 2: Activator
Target for probe 2: Alpha- Glucosidase
Disease relevance for probe 2: Pompe disease
NCBI Book chapter link for probe 2: http://www.ncbi.nlm.nih.gov/books/NBK153221/ (ID: 3046386)
Grant number for probe 2: MH084841-01
NCBI Book chapter title for probe 1: 5-(4-(4-Acetylphenyl)piperazin-1-ylsulfonyl)indolin-2-one Analogs as Inhibitors of Acid alpha-Glucosidase for Potential Chaperone Treatment of Pompe Disease or Intervention for Diabetes Mellitus Type 2
NCBI Book chapter title for probe 2: Discovery, SAR, and Biological Evaluation of a Non-Inhibitory Chaperone for Acid Alpha Glucosidase
Data Table (Concise)