Design and Synthesis of Highly Potent and Selective Pharmacological Chaperones for the Treatment of Gaucher's disease

Compain, Philippe; Martin, Olivier R.; Boucheron, Charlotte; Godin, Guillaume; Yu, Liang; Ikeda, Kyoko; Asano, Naoki

doi:10.1002/cbic.200600217

Cited by 160 publications

(140 citation statements)

References 28 publications

(11 reference statements)

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…In this approach, the chaperone compound binds reversibly to the mutant enzyme, stabilizing its structure and restoring proper trafficking to the lysosome, and then dissociates, allowing the enzyme to metabolize the accumulated substrate. Current efforts to develop small molecule chaperone therapies for Gaucher disease have focused primarily on iminosugar GC substrate analogs (17)(18)(19)(20)(21)(22). However, these molecules can inhibit other glycolipid and glycoprotein processing enzymes and many have fairly low potency and brief half-lives (14,16,26).…”

Section: Discussionmentioning

confidence: 99%

“…The hypothesized mechanism of action for these compounds is competitive binding to the active site of the mutant enzyme, facilitating proper folding and trafficking to the lysosome, where endogenous substrate displaces the chaperone and enzyme activity is restored (8,13,15). Most GC chaperones studied to date are enzyme inhibitors in the structural class of iminosugars or similar analogs of the natural substrate, glucosylceramide (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Iminosugars have been shown to increase the cellular activity of the N370S mutant form of GC, as well as of wild-type enzyme (15,26).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Zheng

Padia

Urban

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

137

130

View full text Add to dashboard Cite

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene. Missense mutations result in reduced enzyme activity that may be due to misfolding, raising the possibility of small-molecule chaperone correction of the defect. Screening large compound libraries by quantitative high-throughput screening (qHTS) provides comprehensive information on the potency, efficacy, and structureactivity relationships (SAR) of active compounds directly from the primary screen, facilitating identification of leads for medicinal chemistry optimization. We used qHTS to rapidly identify three structural series of potent, selective, nonsugar glucocerebrosidase inhibitors. The three structural classes had excellent potencies and efficacies and, importantly, high selectivity against closely related hydrolases. Preliminary SAR data were used to select compounds with high activity in both enzyme and cell-based assays. Compounds from two of these structural series increased N370S mutant glucocerebrosidase activity by 40 -90% in patient cell lines and enhanced lysosomal colocalization, indicating chaperone activity. These small molecules have potential as leads for chaperone therapy for Gaucher disease, and this paradigm promises to accelerate the development of leads for other rare genetic disorders.probe identification ͉ structure-activity relationship ͉ small-molecule inhibitor ͉ chaperone therapy

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Zheng

Padia

Urban

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

137

130

View full text Add to dashboard Cite

show abstract

“…Several glucocerebrosidase variants associated with Gaucher's disease have been shown to be amenable to active-site-directed pharmacologic chaperoning in patient-derived cell lines (Sawkar et al 2002(Sawkar et al , 2006aLin et al 2004;Alfonso et al 2005;Chang et al 2006;Compain et al 2006;Steet et al 2006;Yu et al 2006Yu et al , 2007b. All of the glucocerebrosidase mutants that favorably respond to pharmacologic chaperoning harbor mutations in the active site domain, whereas the L444P mutation, located in the Ig-like domain of glucocerebrosidase, (Dvir et al 2003;Lieberman et al 2007) is not amenable to pharmacologic chaperoning when treated identically.…”

Section: Chemical Strategies To Ameliorate Misfolding and Aggregationmentioning

confidence: 99%

Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Lindquist

Kelly²

2011

Cold Spring Harbor Perspectives in Biology

169

139

View full text Add to dashboard Cite

Maintaining the proteome to preserve the health of an organism in the face of developmental changes, environmental insults, infectious diseases, and rigors of aging is a formidable task. The challenge is magnified by the inheritance of mutations that render individual proteins subject to misfolding and/or aggregation. Maintenance of the proteome requires the orchestration of protein synthesis, folding, degradation, and trafficking by highly conserved/deeply integrated cellular networks. In humans, no less than 2000 genes are involved. Stress sensors detect the misfolding and aggregation of proteins in specific organelles and respond by activating stress-responsive signaling pathways. These culminate in transcriptional and posttranscriptional programs that up-regulate the homeostatic mechanisms unique to that organelle. Proteostasis is also strongly influenced by the general properties of protein folding that are intrinsic to every proteome. These include the kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We then introduce chemical approaches to prevent the misfolding or aggregation of specific proteins through direct binding interactions. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organismal proteostasis.

show abstract

“…The structure of the enzyme is quite unique since all other glycosyltransferases involved in GSL synthesis are localized to the lumenal side of the Golgi apparatus or ER [45]. It catalyzes the transfer of a glucose moiety from UDP-glucose to the primary hydroxyl group of ceramide to yield GlcCer with inversion of the anomeric configuration for synthesis of glucosylceramide [46][47][48].…”

Section: Structure and Functions Of Glucosylceramide Synthase And Glumentioning

confidence: 99%

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Yandım

Apohan

Baran

2012

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDPglucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.

show abstract

Design and Synthesis of Highly Potent and Selective Pharmacological Chaperones for the Treatment of Gaucher's disease

Cited by 160 publications

References 28 publications

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Contact Info

Product

Resources

About