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Organic & Biomolecular Chemistry May 2020Fluorinated carbohydrates, where one (or more) fluorine atom(s) have been introduced into a carbohydrate structure, typically through deoxyfluorination chemistry, have a... (Review)
Review
Fluorinated carbohydrates, where one (or more) fluorine atom(s) have been introduced into a carbohydrate structure, typically through deoxyfluorination chemistry, have a wide range of applications in the glycosciences. Fluorinated derivatives of galactose, glucose, N-acetylgalactosamine, N-acetylglucosamine, talose, fucose and sialic acid have been employed as either donor or acceptor substrates in glycosylation reactions. Fluorinated donors can be synthesised by synthetic methods or produced enzymatically from chemically fluorinated sugars. The latter process is mediated by enzymes such as kinases, phosphorylases and nucleotidyltransferases. Fluorinated donors produced by either method can subsequently be used in glycosylation reactions mediated by glycosyltransferases, or phosphorylases yielding fluorinated oligosaccharide or glycoconjugate products. Fluorinated acceptor substrates are typically synthesised chemically. Glycosyltransferases are most commonly used in conjunction with natural donors to further elaborate fluorinated acceptor substrates. Glycoside hydrolases are used with either fluorinated donors or acceptors. The activity of enzymes towards fluorinated sugars is often lower than towards the natural sugar substrates irrespective of donor or acceptor. This may be in part attributed to elimination of the contribution of the hydroxyl group to the binding of the substrate to enzymes. However, in many cases, enzymes still maintain a significant activity, and reactions may be optimised where necessary, enabling enzymes to be used more successfully in the production of fluorinated carbohydrates. This review describes the current state of the art regarding chemoenzymatic production of fluorinated carbohydrates, focusing specifically on examples of the enzymatic production of activated fluorinated donors and enzymatic glycosylation involving fluorinated sugars as either glycosyl donors or acceptors.
Topics: Carbohydrates; Glycoside Hydrolases; Glycosylation; Glycosyltransferases; Halogenation; Nucleotidyltransferases; Phosphorylases; Phosphotransferases
PubMed: 32319497
DOI: 10.1039/d0ob00436g -
International Journal of Molecular... Jun 2023Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is caused by a deficiency of the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) enzyme, leading to the...
Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is caused by a deficiency of the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) enzyme, leading to the accumulation of glycosaminoglycans (GAG), keratan sulfate (KS) and chondroitin-6-sulfate (C6S), mainly in cartilage and bone. This lysosomal storage disorder (LSD) is characterized by severe systemic skeletal dysplasia. To this date, none of the treatment options for the MPS IVA patients correct bone pathology. Enzyme replacement therapy with elosulfase alpha provides a limited impact on bone growth and skeletal lesions in MPS IVA patients. To improve bone pathology, we propose a novel gene therapy with a small peptide as a growth-promoting agent for MPS IVA. A small molecule in this peptide family has been found to exert biological actions over the cardiovascular system. This work shows that an AAV vector expressing a C-type natriuretic (CNP) peptide induces bone growth in the MPS IVA mouse model. Histopathological analysis showed the induction of chondrocyte proliferation. CNP peptide also changed the pattern of GAG levels in bone and liver. These results suggest the potential for CNP peptide to be used as a treatment in MPS IVA patients.
Topics: Animals; Mice; Mucopolysaccharidosis IV; Keratan Sulfate; Glycosaminoglycans; Cartilage; Bone Development
PubMed: 37373036
DOI: 10.3390/ijms24129890 -
International Journal of Molecular... Nov 2023Mucopolysaccharidosis IVA (MPS IVA) is a rare disorder caused by mutations in the N-acetylgalactosamine-6-sulfate-sulfatase () encoding gene. GALNS leads to the... (Review)
Review
Mucopolysaccharidosis IVA (MPS IVA) is a rare disorder caused by mutations in the N-acetylgalactosamine-6-sulfate-sulfatase () encoding gene. GALNS leads to the lysosomal degradation of the glycosaminoglyccreasans keratan sulfate and chondroitin 6-sulfate. Impaired GALNS enzymes result in skeletal and non-skeletal complications in patients. For years, the MPS IVA pathogenesis and the assessment of promising drugs have been evaluated using in vitro (primarily fibroblasts) and in vivo (mainly mouse) models. Even though value information has been raised from those studies, these models have several limitations. For instance, chondrocytes have been well recognized as primary cells affected in MPS IVA and responsible for displaying bone development impairment in MPS IVA patients; nonetheless, only a few investigations have used those cells to evaluate basic and applied concepts. Likewise, current animal models are extensively represented by mice lacking GALNS expression; however, it is well known that MPS IVA mice do not recapitulate the skeletal dysplasia observed in humans, making some comparisons difficult. This manuscript reviews the current in vitro and in vivo MPS IVA models and their drawbacks.
Topics: Humans; Mice; Animals; Mucopolysaccharidosis IV; Keratan Sulfate; Chondroitin Sulfates; Chondrocytes; Disease Models, Animal; Chondroitinsulfatases
PubMed: 38003337
DOI: 10.3390/ijms242216148 -
RSC Advances Sep 2019Naturally extracted glycosaminoglycan chondroitin sulphate is the reactive product of -acetylgalactosamine and d-glucuronic acid. Chondroitin sulfate (CS) extracted from... (Review)
Review
Naturally extracted glycosaminoglycan chondroitin sulphate is the reactive product of -acetylgalactosamine and d-glucuronic acid. Chondroitin sulfate (CS) extracted from , , , , and has shown remarkable anticoagulant, articular cartilage repair, corneal lesion healing, antidiabetic, and antiproliferative effects. Also, platinum and strontium nanoparticles of chondroitin sulfate are effective in osteoarthritis and exert anti-HSV2 and anti-angiogenic properties. A combination of chondroitin sulfate and RNA lipolexes demonstrates gene silencing effects in liver fibrosis. Chondroitin sulfate has also been used as a carrier for loxoprofen hydrogel preparation. Oligosaccharides of chondroitin sulfate showed effective inhibition of bovine testicular hyaluronidase enzyme as an antibacterial agent during pregnancy. Monoclonal antibody-recognized chondroitin sulfate A was effectively used to treat ameloblastoma. Selenium-chondroitin sulfate nanoparticles demonstrated positive effects in therapy of Kashin-Beck disease (KBD) and osteoarthritis.
PubMed: 35530463
DOI: 10.1039/c9ra05546k -
Current Opinion in Lipidology Dec 2023The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition studies.
RECENT FINDINGS
The clinical development of vupanorsen, a N-acetylgalactosamine (GalNAc) antisense targeting hepatic ANGPTL3, was recently discontinued due to a significant signal of liver transaminase increase. Vupanorsen elicited a dose-dependent increase in hepatic fat fraction up to 75%, whereas the small interfering RNA (siRNA) ARO-ANG3, has reported preliminary evidence of a dose-dependent decrease in hepatic fat fraction up to 30%.
SUMMARY
ANGPTL3 inhibition is an attractive therapeutic target to reduce all apoB-containing lipoproteins. The discrepancy in liver signal results between the antisense and siRNA approach may be explained by the level of target inhibition. An alternative explanation may relate to off-target effects of vupanorsen, which have a molecule- and/or platform-specific origin. For intrahepatic strategies, highly potent ANGPTL3 inhibition will for now require special attention for liver safety.
Topics: Humans; Angiopoietin-like Proteins; Angiopoietin-Like Protein 3; Liver; RNA, Small Interfering; Angiopoietins
PubMed: 37820081
DOI: 10.1097/MOL.0000000000000898 -
International Journal of Molecular... Jul 2020The large family of C-type lectin (CLEC) receptors comprises carbohydrate-binding proteins that require Ca to bind a ligand. The prototypic receptor is the... (Review)
Review
The large family of C-type lectin (CLEC) receptors comprises carbohydrate-binding proteins that require Ca to bind a ligand. The prototypic receptor is the asialoglycoprotein receptor-1 (ASGR1, CLEC4H1) that is expressed primarily by hepatocytes. The early work on ASGR1, which is highly specific for N-acetylgalactosamine (GalNAc), established the foundation for understanding the overall function of CLEC receptors. Cells of the immune system generally express more than one CLEC receptor that serve diverse functions such as pathogen-recognition, initiation of cellular signaling, cellular adhesion, glycoprotein turnover, inflammation and immune responses. The receptor CLEC10A (C-type lectin domain family 10 member A, CD301; also called the macrophage galactose-type lectin, MGL) contains a carbohydrate-recognition domain (CRD) that is homologous to the CRD of ASGR1, and thus, is also specific for GalNAc. CLEC10A is most highly expressed on immature DCs, monocyte-derived DCs, and alternatively activated macrophages (subtype M2a) as well as oocytes and progenitor cells at several stages of embryonic development. This receptor is involved in initiation of T1, T2, and T17 immune responses and induction of tolerance in naïve T cells. Ligand-mediated endocytosis of CLEC receptors initiates a Ca signal that interestingly has different outcomes depending on ligand properties, concentration, and frequency of administration. This review summarizes studies that have been carried out on these receptors.
Topics: Animals; Asialoglycoprotein Receptor; Calcium Signaling; Dendritic Cells; Embryonic Development; Humans; Immunity; Lectins, C-Type; Ligands; Macrophages; T-Lymphocytes
PubMed: 32650396
DOI: 10.3390/ijms21144818 -
Current Opinion in Chemical Biology Apr 2021UDP-glucose 4-epimerase (GalE) catalyzes the interconversion of UDP-glucose (UDP-Glc) and UDP-galactose (UDP-Gal) and/or the interconversion of UDP-N-acetylglucosamine... (Review)
Review
UDP-glucose 4-epimerase (GalE) catalyzes the interconversion of UDP-glucose (UDP-Glc) and UDP-galactose (UDP-Gal) and/or the interconversion of UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc) in sugar metabolism. GalEs belong to the short-chain dehydrogenase/reductase superfamily, use a conserved 'transient keto intermediate' mechanism and have variable substrate specificity. GalEs have been classified into three groups based on substrate specificity: group 1 prefers UDP-Glc/Gal, group 3 prefers UDP-GlcNAc/GalNAc, and group 2 has comparable activities for both types of the substrates. The phylogenetic relationship and structural basis for the specificities of GalEs revealed possible molecular evolution of UDP-hexose 4-epimerases in various organisms. Based on the recent advances in studies on GalEs and related enzymes, an updated view of their evolutional diversification is presented.
Topics: Evolution, Molecular; Racemases and Epimerases; Substrate Specificity; Uridine Diphosphate
PubMed: 33171387
DOI: 10.1016/j.cbpa.2020.09.007 -
Current Atherosclerosis Reports Oct 2022Plasma levels of LDL cholesterol (LDL-C) are causally associated with cardiovascular risk. Reducing LDL-C results in a decreased incidence of cardiovascular events,... (Review)
Review
PURPOSE OF REVIEW
Plasma levels of LDL cholesterol (LDL-C) are causally associated with cardiovascular risk. Reducing LDL-C results in a decreased incidence of cardiovascular events, proportionally to the absolute reduction in LDL-C. The inhibition of proprotein convertase subtilisin kexin 9 (PCSK) is a highly effective and safe approach to reducing LDL-C levels. In this review, we discuss the available data on the efficacy and safety of inclisiran, a siRNA targeting PCSK9 and propose a clinical profile for the patients who can benefit the most from this approach.
RECENT FINDINGS
Inclisiran is a small interfering RNA targeting the mRNA of PCSK9 specifically in the liver, owing to the conjugation with triantennary N-acetylgalactosamine. Randomized clinical trials have shown that inclisiran provides robust and durable reductions of PCSK9 and LDL-C levels, with a dosing schedule of once every 6 months after the initial and 3-month doses. These effects are consistent in different categories of patients, including patients with atherosclerotic cardiovascular disease and/or risk equivalent or patients with heterozygous familial hypercholesterolaemia. Ultimately the administration schedule may improve patients' compliance given also the favourable safety profile of the drug. Completion of ongoing outcome clinical trials will provide information on both the expected clinical benefit and the safety of inclisiran administered for longer.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Humans; PCSK9 Inhibitors; Proprotein Convertase 9; RNA, Small Interfering
PubMed: 35877035
DOI: 10.1007/s11883-022-01056-0 -
ACS Omega Jun 2021The potential therapeutic application of oligonucleotides (ONs) that selectively suppress target genes through antisense and RNA interference mechanisms has attracted... (Review)
Review
The potential therapeutic application of oligonucleotides (ONs) that selectively suppress target genes through antisense and RNA interference mechanisms has attracted great attention. The clinical applications of ONs have overcome multiple obstacles and become one of the most active areas for the development of novel therapeutics. To achieve efficient and specific cellular internalization, conjugation of a variety of functional groups to ONs has been the subject of intensive investigations over the past decade. Among them, a promising liver-targeted -acetylgalactosamine (GalNAc) ligand has been evaluated in multiple preclinical and clinical trials for improving the cellular uptake and tissue specific delivery of ONs. GalNAc-based delivery relies on the fact that liver hepatocytes abundantly and specifically express the asialoglycoprotein receptor that binds and uptakes circulating glycoproteins via receptor-mediated endocytosis. In recent years, encouraging progress has been made in the field of GalNAc conjugates. This review aims to provide an overview of GalNAc-mediated liver-targeted delivery of small interfering RNA and antisense oligonucleotides, and the immense effort as well as recent advances in the development of GalNAc-conjugated agents are described.
PubMed: 34235295
DOI: 10.1021/acsomega.1c01755 -
Drugs Oct 2023Silencing the transthyretin (TTR) gene is an effective strategy in the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis. Vutrisiran (Amvuttra), an RNA... (Review)
Review
Silencing the transthyretin (TTR) gene is an effective strategy in the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis. Vutrisiran (Amvuttra), an RNA interference (RNAi) therapeutic targeting TTR mRNA, is approved in the USA and EU for the treatment of adults with polyneuropathy of hATTR amyloidosis. N-acetylgalactosamine conjugation and enhanced stabilisation chemistry are utilised to target vutrisiran to the liver and increase stability, respectively, allowing for subcutaneous administration once every 3 months. In a pivotal phase 3 study in patients with hATTR amyloidosis with polyneuropathy, subcutaneous vutrisiran 25 mg every 3 months significantly reduced neuropathy impairment versus external placebo. Vutrisiran was also associated with significant improvements in neuropathy-specific quality of life, gait speed, nutritional status and disability scores. Vutrisiran was generally well tolerated; the only common adverse events to occur at a greater incidence than with external placebo were pain in extremity and arthralgia. Vutrisiran reduces serum vitamin A levels and vitamin A supplementation is recommended. In conclusion, vutrisiran is an efficacious and generally well-tolerated alternative option for the treatment of polyneuropathy of hATTR amyloidosis, which has the potential advantage of infrequent subcutaneous dosage.
Topics: Adult; Humans; Quality of Life; Prealbumin; Vitamin A; Amyloid Neuropathies, Familial; Polyneuropathies
PubMed: 37728865
DOI: 10.1007/s40265-023-01943-z