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Signal Transduction and Targeted Therapy Jun 2020RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a... (Review)
Review
RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.
Topics: Acetylgalactosamine; Genetic Diseases, Inborn; Genetic Therapy; Humans; Pyrrolidines; RNA Interference; RNA, Double-Stranded; RNA, Small Interfering
PubMed: 32561705
DOI: 10.1038/s41392-020-0207-x -
Genes Apr 2023The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate--acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for - or -linked... (Review)
Review
The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate--acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for - or -linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and -acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for -glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how -GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein -glycosylation and -GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.
Topics: Hexosamines; Protein Processing, Post-Translational; Glucosamine; Glycosylation; TOR Serine-Threonine Kinases
PubMed: 37107691
DOI: 10.3390/genes14040933 -
Glycoconjugate Journal Jun 2023The structure and properties of a group of gangliosides modified by mild alkaline treatment are discussed. We will present the occurrence and the structure of... (Review)
Review
The structure and properties of a group of gangliosides modified by mild alkaline treatment are discussed. We will present the occurrence and the structure of gangliosides carrying the N-acetyneuraminic acid O-acetylated in position 9, the Neu5,9Ac, and of gangliosides carrying a sialic acid that forms a lactone ring. Starting from biochemical data we will discuss the possible biochemical role played by these gangliosides in the processes of cell signaling and maintenance of brain functions.
Topics: Gangliosides; N-Acetylneuraminic Acid; Sialic Acids; Acetylation
PubMed: 36695939
DOI: 10.1007/s10719-023-10103-0 -
Journal of Medicinal Chemistry Oct 2022Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By... (Review)
Review
Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for understanding sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors.
Topics: Humans; Neuraminidase; Zanamivir; Oseltamivir; N-Acetylneuraminic Acid; Enzyme Inhibitors; Sialic Acids; Antiviral Agents; Biological Products
PubMed: 36252951
DOI: 10.1021/acs.jmedchem.2c01258 -
International Journal of Molecular... Sep 2022Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure... (Review)
Review
Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field.
Topics: Acetylglucosamine; Hexosamines; Homeostasis; Kidney; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational
PubMed: 36232558
DOI: 10.3390/ijms231911260 -
Glycobiology Oct 2022N-glycolylated carbohydrates are amino sugars with an N-glycolyl amide group. These glycans have not been well studied due to their surprising rarity in nature in... (Review)
Review
N-glycolylated carbohydrates are amino sugars with an N-glycolyl amide group. These glycans have not been well studied due to their surprising rarity in nature in comparison with N-acetylated carbohydrates. Recently, however, there has been increasing interest in N-glycolylated sugars because the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc), apparently the only source of all N-glycolylated sugars in deuterostomes, appears to be involved in xenosialitis (inflammation associated with consumption of Neu5Gc-rich red meats). Xenosialitis has been implicated in cancers as well as other diseases including atherosclerosis. Furthermore, metabolites of Neu5Gc have been shown to be incorporated into glycosaminoglycans (GAGs), resulting in N-glycolylated GAGs. These N-glycolylated GAGs have important potential applications, such as dating the loss of the Neu5Gc-generating CMAH gene in humans and being explored as a xenosialitis biomarker and/or estimate of the body burden of diet-derived Neu5Gc, to understand the risks associated with the consumption of red meats. This review explores N-glycolylated carbohydrates, how they are metabolized to N-glycolylglucosamine and N-glycolylgalactosamine, and how these metabolites can be incorporated into N-glycolylated GAGs in human tissues. We also discuss other sources of N-glycolylated sugars, such as recombinant production from microorganisms using metabolic engineering as well as chemical synthesis.
Topics: Humans; Neuraminic Acids; N-Acetylneuraminic Acid; Amino Sugars; Polysaccharides; Inflammation
PubMed: 35925816
DOI: 10.1093/glycob/cwac048 -
Molecules (Basel, Switzerland) Feb 2023Microbial production of hyaluronic acid (HA) is an area of research that has been gaining attention in recent years due to the increasing demand for this biopolymer for... (Review)
Review
Microbial production of hyaluronic acid (HA) is an area of research that has been gaining attention in recent years due to the increasing demand for this biopolymer for several industrial applications. Hyaluronic acid is a linear, non-sulfated glycosaminoglycan that is widely distributed in nature and is mainly composed of repeating units of N-acetylglucosamine and glucuronic acid. It has a wide and unique range of properties such as viscoelasticity, lubrication, and hydration, which makes it an attractive material for several industrial applications such as cosmetics, pharmaceuticals, and medical devices. This review presents and discusses the available fermentation strategies to produce hyaluronic acid.
Topics: Hyaluronic Acid; Fermentation; Chemical Phenomena; Acetylglucosamine; Glucuronic Acid
PubMed: 36903332
DOI: 10.3390/molecules28052084 -
Advances in Carbohydrate Chemistry and... 2023Fructosamine has long been considered as a key intermediate of the Maillard reaction, which to a large extent is responsible for specific aroma, taste, and color...
Fructosamine has long been considered as a key intermediate of the Maillard reaction, which to a large extent is responsible for specific aroma, taste, and color formation in thermally processed or dehydrated foods. Since the 1980s, however, as a product of the Amadori rearrangement reaction between glucose and biologically significant amines such as proteins, fructosamine has experienced a boom in biomedical research, mainly due to its relevance to pathologies in diabetes and aging. In this chapter, we assess the scope of the knowledge on and applications of fructosamine-related molecules in chemistry, food, and health sciences, as reflected mostly in publications within the past decade. Methods of fructosamine synthesis and analysis, its chemical, and biological properties, and degradation reactions, together with fructosamine-modifying and -recognizing proteins are surveyed.
Topics: Humans; Fructosamine; Fructose; Maillard Reaction; Proteins; Diabetes Mellitus
PubMed: 37968038
DOI: 10.1016/bs.accb.2023.10.002 -
Bioconjugate Chemistry Apr 2022-Acetyl-β-d-hexosaminidases (EC 3.2.1.52) are exo-acting glycosyl hydrolases that remove -acetyl-β-d-glucosamine (Glc-NAc) or -acetyl-β-d-galactosamine (Gal-NAc) from... (Review)
Review
-Acetyl-β-d-hexosaminidases (EC 3.2.1.52) are exo-acting glycosyl hydrolases that remove -acetyl-β-d-glucosamine (Glc-NAc) or -acetyl-β-d-galactosamine (Gal-NAc) from the nonreducing ends of various biomolecules including oligosaccharides, glycoproteins, and glycolipids. The same enzymes are sometimes called -acetyl-β-d-glucosaminidases, and this review article employs the shorthand descriptor HEX(NAG) to indicate that the terms HEX or NAG are used interchangeably in the literature. The wide distribution of HEX(NAG) throughout the biosphere and its intracellular location in lysosomes combine to make it an important enzyme in food science, agriculture, cell biology, medical diagnostics, and chemotherapy. For more than 50 years, researchers have employed chromogenic derivatives of -acetyl-β-d-glucosaminide in basic assays for biomedical research and clinical chemistry. Recent conceptual and synthetic innovations in molecular fluorescence sensors, along with concurrent technical improvements in instrumentation, have produced a growing number of new fluorescent imaging and diagnostics methods. A systematic summary of the recent advances in optical sensors for HEX(NAG) is provided under the following headings: assessing kidney health, detection and treatment of infectious disease, fluorescence imaging of cancer, treatment of lysosomal disorders, and reactive probes for chemical biology. The article concludes with some comments on likely future directions.
Topics: Acetylglucosaminidase; Glucosamine; Glycolipids; Hydrolases; beta-N-Acetylhexosaminidases
PubMed: 35302753
DOI: 10.1021/acs.bioconjchem.2c00057 -
The Journal of Biological Chemistry Apr 2022Nucleotide sugar (NS) dehydratases play a central role in the biosynthesis of deoxy and amino sugars, which are involved in a variety of biological functions in all... (Review)
Review
Nucleotide sugar (NS) dehydratases play a central role in the biosynthesis of deoxy and amino sugars, which are involved in a variety of biological functions in all domains of life. Bacteria are true masters of deoxy sugar biosynthesis as they can produce a wide range of highly specialized monosaccharides. Indeed, deoxy and amino sugars play important roles in the virulence of gram-positive and gram-negative pathogenic species and are additionally involved in the biosynthesis of diverse macrolide antibiotics. The biosynthesis of deoxy sugars relies on the activity of NS dehydratases, which can be subdivided into three groups based on their structure and reaction mechanism. The best-characterized NS dehydratases are the 4,6-dehydratases that, together with the 5,6-dehydratases, belong to the NS-short-chain dehydrogenase/reductase superfamily. The other two groups are the less abundant 2,3-dehydratases that belong to the Nudix hydrolase superfamily and 3-dehydratases, which are related to aspartame aminotransferases. 4,6-Dehydratases catalyze the first step in all deoxy sugar biosynthesis pathways, converting nucleoside diphosphate hexoses to nucleoside diphosphate-4-keto-6-deoxy hexoses, which in turn are further deoxygenated by the 2,3- and 3-dehydratases to form dideoxy and trideoxy sugars. In this review, we give an overview of the NS dehydratases focusing on the comparison of their structure and reaction mechanisms, thereby highlighting common features, and investigating differences between closely related members of the same superfamilies.
Topics: Hydro-Lyases; Nucleosides; Nucleotides; Substrate Specificity; Sugars
PubMed: 35271853
DOI: 10.1016/j.jbc.2022.101809