The glycome describes the complete repertoire of glycoconjugates composed of carbohydrate chains, or glycans, that are covalently linked to lipid or protein molecules. Glycoconjugates are formed through a process called glycosylation and can differ in their glycan sequences, the connections between them and their length. Glycoconjugate synthesis is a dynamic process that depends on the local milieu of enzymes, sugar precursors and organelle structures as well as the cell types involved and cellular signals. Studies of rare genetic disorders that affect glycosylation first highlighted the biological importance of the glycome, and technological advances have improved our understanding of its heterogeneity and complexity. Researchers can now routinely assess how the secreted and cell-surface glycomes reflect overall cellular status in health and disease. In fact, changes in glycosylation can modulate inflammatory responses, enable viral immune escape, promote cancer cell metastasis or regulate apoptosis; the composition of the glycome also affects kidney function in health and disease. New insights into the structure and function of the glycome can now be applied to therapy development and could improve our ability to fine-tune immunological responses and inflammation, optimize the performance of therapeutic antibodies and boost immune responses to cancer. These examples illustrate the potential of the emerging field of ‘glycomedicine’. Glycosylation refers to the addition of carbohydrate chains to proteins and lipids. In this Review, the authors discuss the broad role of glycans in immunity, cancer, xenotransplantation and glomerular filtration and the potential of ‘glycomedicine’.

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Glycosylation in health and disease.

The discovery of the glycosphingolipids is generally attributed to Johan L. W. Thudichum, who in 1884 published on the chemical composition of the brain. In his studies he isolated several compounds from ethanolic brain extracts which he coined cerebrosides. He subjected one of these, phrenosin (now known as galactosylceramide), to acid hydrolysis, and this produced three distinct components. One he identified as a fatty acid and another proved to be an isomer of D-glucose, which is now known as D-galactose. The third component, with an "alkaloidal nature", presented "many enigmas" to Thudichum, and therefore he named it sphingosine, after the mythological riddle of the Sphinx. Today, sphingolipids and their glycosidated derivatives are the subjects of intense study aimed at elucidating their role in the structural integrity of the cell membrane, their participation in recognition and signaling events, and in particular their involvement in pathological processes that are at the basis of human disease (for example, sphingolipidoses and diabetes type 2). This Review details some of the recent findings on the biosynthesis, function, and degradation of glycosphingolipids in man, with a focus on the glycosphingolipid glucosylceramide. Special attention is paid to the clinical relevance of compounds directed at interfering with the factors responsible for glycosphingolipid metabolism.

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

Inhibitors of sphingolipid metabolism enzymes.

The chemical-chaperone approach is an emerging concept in drug research that holds promise for the treatment of inherited diseases caused by improperly folded proteins. This strategy is based on the capacity of certain low-molecular-weight compounds to stabilize or alter the three-dimensional architecture of defective proteins. Recently, the effectiveness of the chemical-chaperone concept has been demonstrated in the field of lysosomal-storage disorders, a group of more than 40 rare diseases that are characterized by the deficiency of the glycosidases involved in the catabolism of glycosphingolipids in the lysosome. In 1999, it was reported that the residual agalactosidase A activity in the lymphoblasts of patients with Fabry disease could be significantly enhanced by using iminosugar-based inhibitors of the deficient glycosidase at subinhibitory concentrations. This “nonintuitive” result can be explained by the fact that, even though the defective enzyme is predisposed to misfolding and/or instability, it is still catalytically active. Reversible competitive inhibitors positively influence the folding state of the abnormal enzyme, thus preventing its degradation by quality control in the endoplasmic reticulum (ER) and ER-associated degradation (ERAD) before its transfer to lysosomes. According to the so-called threshold theory, the severity of the disease correlates with the residual degrading capacity in the patients’ lysosomes and, therefore, even a slight elevation in enzyme activity can lead to a significant improvement in the symptoms associated with a lysosomal-storage disorder. Active-site-specific chaperone strategies are being evaluated clinically for the treatment of Fabry disease, thus highlighting their strong potential as a new therapeutic option for these disorders. Recent studies have shown that this approach may be applied to Gaucher’s disease, the most prevalent lysosomal-storage disorder. 7] This autosomal recessive disease is caused by a deficiency of glucosylceramide b-glucosidase, also called bglucocerebrosidase, (GCase) that leads to the accumulation of undegraded glucosylceramide (GlcCer), especially in macrophages, and to severe symptoms. In type 1, the mildest and most common of the three clinical forms of Gaucher’s disease, patients suffer from bone pain, skeletal lesions, anaemia and liver or spleen damage. The first-line treatment for Gaucher’s disease is based on the administration of CerezymeA, a recombinant form of GCase, to supplement the defective hydrolytic enzyme. A second strategy makes use of a small molecule, N-butyl-1-deoxynojirimycin 1 (NB-DNJ, ZavescaA), to inhibit the biosynthesis of GlcCer.

Design and synthesis of highly potent and selective pharmacological chaperones for the treatment of Gaucher's disease.

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 structure–activity 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.

https://www.pnas.org/content/pnas/104/32/13192.full.pdf

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

Rational design and synthesis of highly potent beta-glucocerebrosidase inhibitors.

Rational Design and Synthesis of Highly Potent β‐Glucocerebrosidase Inhibitors

The present invention provides glucoimidazole (GIZ) and polyhydroxycyclohexenyl amine (PHCA) derivatives, methods of making them, and methods of use where the GIZ and PHCA derivatives have a short, flexible linker emanating from the corresponding position of the ring oxygen in a pyranose; and a lipophilic moiety connected to the linker and pharmaceutically acceptable salts thereof. More particularly, the present invention further provides a method for treating individuals having Gaucher disease by administering the novel GIZ or PHCA derivatives as “chaperones” for the mutant glucocerebrosidase associated with the disease.

Glucoimidazole and polyhydroxycyclohexenyl amine derivatives to treat gaucher disease

The present invention provides novel hydroxy piperidine (HP) derivatives having (i) a positive charge at the position corresponding to the anomeric position of a pyranose ring; (ii) a short, flexible linker emanating from the corresponding position of the ring oxygen in a pyranose; and (iii) a lipophilic moiety connected to the linker and pharmaceutically acceptable salts thereof The linker can be absent if the lipophilic moiety corresponds to a hydrocarbon chain with a linear length of 6 or more carbons The present invention further provides a method for treating individuals having Gaucher disease by administering the novel HP derivative as 'chaperones' for the mutant glucocerebrosidase associated with the disease

Hydroxy piperidine derivatives to treat gaucher disease

A method for preparing isofagomine, its derivatives, intermediates and salts thereof using novel processes to make isofagomine from D-(−)-arabinose and L-(−)-xylose.

Xiaoxiang Zhu

Papers

Rational design and synthesis of highly potent beta-glucocerebrosidase inhibitors.

Rational Design and Synthesis of Highly Potent β‐Glucocerebrosidase Inhibitors

Glucoimidazole and polyhydroxycyclohexenyl amine derivatives to treat gaucher disease

Hydroxy piperidine derivatives to treat gaucher disease

New method for preparing isofagomine and its derivatives