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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 -
Physiological Reviews Apr 2021In the mid-1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by a -acetylglucosamine moiety (-GlcNAc) via an... (Review)
Review
In the mid-1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by a -acetylglucosamine moiety (-GlcNAc) via an -linkage overturned the widely held assumption that glycosylation only occurred in the endoplasmic reticulum, Golgi apparatus, and secretory pathways. In contrast to traditional glycosylation, the -GlcNAc modification does not lead to complex, branched glycan structures and is rapidly cycled on and off proteins by -GlcNAc transferase (OGT) and -GlcNAcase (OGA), respectively. Since its discovery, -GlcNAcylation has been shown to contribute to numerous cellular functions, including signaling, protein localization and stability, transcription, chromatin remodeling, mitochondrial function, and cell survival. Dysregulation in -GlcNAc cycling has been implicated in the progression of a wide range of diseases, such as diabetes, diabetic complications, cancer, cardiovascular, and neurodegenerative diseases. This review will outline our current understanding of the processes involved in regulating -GlcNAc turnover, the role of -GlcNAcylation in regulating cellular physiology, and how dysregulation in -GlcNAc cycling contributes to pathophysiological processes.
Topics: Acetylglucosamine; Animals; Cell Physiological Phenomena; Glycosylation; Humans; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational
PubMed: 32730113
DOI: 10.1152/physrev.00043.2019 -
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 -
Cell Host & Microbe Oct 2022The pattern-recognition receptor NOD2 senses bacterial muropeptides to regulate host immunity and maintain homeostasis. Loss-of-function mutations in NOD2 are associated...
The pattern-recognition receptor NOD2 senses bacterial muropeptides to regulate host immunity and maintain homeostasis. Loss-of-function mutations in NOD2 are associated with Crohn's disease (CD), but how the variations in microbial factors influence NOD2 signaling and host pathology is elusive. We demonstrate that the Firmicutes peptidoglycan remodeling enzyme, DL-endopeptidase, increased the NOD2 ligand level in the gut and impacted colitis outcomes. Metagenomic analyses of global cohorts (n = 857) revealed that DL-endopeptidase gene abundance decreased globally in CD patients and negatively correlated with colitis. Fecal microbiota from CD patients with low DL-endopeptidase activity predisposed mice to colitis. Administering DL-endopeptidase, but not an active site mutant, alleviated colitis via the NOD2 pathway. Therapeutically restoring NOD2 ligands with a DL-endopeptidase-producing Lactobacillus salivarius strain or mifamurtide, a clinical analog of muramyl dipeptide, exerted potent anti-colitis effects. Our study suggests that the depletion of DL-endopeptidase contributes to CD pathogenesis through NOD2 signaling, providing a therapeutically modifiable target.
Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Colitis; Crohn Disease; Endopeptidases; Gastrointestinal Microbiome; Ligands; Mice; Nod2 Signaling Adaptor Protein; Peptidoglycan
PubMed: 36049483
DOI: 10.1016/j.chom.2022.08.002 -
Molecular Aspects of Medicine Jun 2021Polysialic acid (polySia, PSA) is a unique constituent of the glycocalyx on the surface of bacterial and vertebrate cells. In vertebrates, its biosynthesis is highly... (Review)
Review
Polysialic acid (polySia, PSA) is a unique constituent of the glycocalyx on the surface of bacterial and vertebrate cells. In vertebrates, its biosynthesis is highly regulated, not only in quantity and quality, but also in time and location, which allows polySia to be involved in various important biological phenomena. Therefore, impairments in the expression and structure of polySia sometimes relate to diseases, such as schizophrenia, bipolar disorder, and cancer. Some bacteria express polySia as a tool for protecting themselves from the host immune system during invasion. PolySia is proven to be a biosafe material; polySia, as well as polySia-recognizing molecules, are key therapeutic agents. This review first comprehensive outlines the occurrence, features, biosynthesis, and functions of polySia and subsequently focuses on the related diseases.
Topics: Animals; Glycocalyx; Humans; Sialic Acids; Sialyltransferases
PubMed: 32863045
DOI: 10.1016/j.mam.2020.100892 -
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 -
Science Advances May 2023Sialic acids linked to glycoproteins and glycolipids are important mediators of cell and protein recognition events. These sugar residues are removed by neuraminidases...
Sialic acids linked to glycoproteins and glycolipids are important mediators of cell and protein recognition events. These sugar residues are removed by neuraminidases (sialidases). Neuraminidase-1 (sialidase-1 or NEU1) is a ubiquitously expressed mammalian sialidase located in lysosomes and on the cell membrane. Because of its modulation of multiple signaling processes, it is a potential therapeutic target for cancers and immune disorders. Genetic defects in NEU1 or in its protective protein cathepsin A (PPCA, CTSA) cause the lysosomal storage diseases sialidosis and galactosialidosis. To further our understanding of this enzyme's function at the molecular level, we determined the three-dimensional structure of murine NEU1. The enzyme oligomerizes through two self-association interfaces and displays a wide substrate-binding cavity. A catalytic loop adopts an inactive conformation. We propose a mechanism of activation involving a conformational change in this loop upon binding to its protective protein. These findings may facilitate the development of selective inhibitor and agonist therapies.
Topics: Animals; Mice; Cell Membrane; Lysosomes; Neuraminidase; Sialic Acids
PubMed: 37205763
DOI: 10.1126/sciadv.adf8169 -
International Journal of Molecular... Oct 2020The so-called "" has become an attractive research area, as an increasing number of natural products containing a sialic acid moiety have been shown to play important... (Review)
Review
The so-called "" has become an attractive research area, as an increasing number of natural products containing a sialic acid moiety have been shown to play important roles in biological, pathological, and immunological processes. The intramolecular lactones of sialic acids are a subclass from this crucial family that could have central functions in the discrimination of physiological and pathological conditions. In this review, we report an in-depth analysis of the synthetic achievements in the preparation of the intramolecular lactones of sialic acids (1,4-, 1,7- and γ-lactones), in their free and/or protected form. In particular, recent advances in the synthesis of the 1,7-lactones have allowed the preparation of key sialic acid derivatives. These compounds could be used as authentic reference standards for their correct determination in biological samples, thus overcoming some of the limitations of the previous analytical procedures.
Topics: Lactones; Sialic Acids
PubMed: 33143039
DOI: 10.3390/ijms21218098