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Drugs Apr 2021Fabry disease (FD) is a rare X-linked lysosomal storage disease based on a deficiency of α-galactosidase A (AGAL) caused by mutations in the α-galactosidase A gene... (Review)
Review
Fabry disease (FD) is a rare X-linked lysosomal storage disease based on a deficiency of α-galactosidase A (AGAL) caused by mutations in the α-galactosidase A gene (GLA). The lysosomal accumulation of glycosphingolipids, especially globotriaosylceramide (Gb) and globotriaosylsphingosine (lyso-Gb, deacylated form), leads to a multisystemic disease with progressive renal failure, cardiomyopathy with potentially malignant cardiac arrhythmias, and strokes, which considerably limits the life expectancy of affected patients. Diagnostic confirmation in male patients is based on the detection of AGAL deficiency in blood leukocytes, whereas in women, due to the potentially high residual enzymatic activity, molecular genetic detection of a causal mutation is required. Current treatment options for FD include recombinant enzyme replacement therapy (ERT) with intravenous agalsidase-alfa (0.2 mg/kg body weight) or agalsidase-beta (1 mg/kg body weight) every 2 weeks and oral chaperone therapy with migalastat (123 mg every other day), which selectively and reversibly binds to the active site of AGAL, thereby correcting the misfolding of the enzyme and allowing it to traffic to the lysosome. These therapies enable cellular Gb clearance and improve the burden of disease. However, in about 40% of all ERT-treated men, ERT can lead to infusion-associated reactions and the formation of neutralizing antidrug antibodies, which reduces the efficacy of therapy. In chaperone therapy, there are carriers of amenable mutations that show limited clinical success. This article provides a brief overview of the clinical picture in FD patients, diagnostic confirmation, and interdisciplinary clinical management of FD. The focus is on current and future therapeutic options.
Topics: 1-Deoxynojirimycin; Enzyme Replacement Therapy; Fabry Disease; Humans; Isoenzymes; Recombinant Proteins; alpha-Galactosidase
PubMed: 33721270
DOI: 10.1007/s40265-021-01486-1 -
International Journal of Antimicrobial... Sep 2020Using antiseptics in wound care can promote healing by preventing and treating infection. However, using antiseptics can present many challenges, including issues with... (Review)
Review
OBJECTIVES
Using antiseptics in wound care can promote healing by preventing and treating infection. However, using antiseptics can present many challenges, including issues with tolerability, inactivation by organic matter and the emergence of antimicrobial resistance/cross-resistance. This review discussed the key challenges in antisepsis, focusing on povidone-iodine (PVP-I) antiseptic.
METHODS
Literature searches were conducted in PubMed, in January 2019, with a filter for the previous 5 years. Searches were based on the antimicrobial efficacy, antiseptic resistance, wound healing properties, and skin tolerability for the commonly used antiseptics PVP-I, chlorhexidine gluconate (CHG), polyhexanide (PHMB), and octenidine (OCT). Additional papers were identified based on author expertise.
RESULTS
When compared with CHG, PHMB and OCT, PVP-I had a broader spectrum of antimicrobial activity against Gram-negative bacteria, actinobacteria, bacterial spores, fungi and viruses, and a similar and broad spectrum of activity against Gram-positive bacteria. PVP-I was also highly effective at eradicating bacterial biofilms, which is a vitally important consideration for wound care and infection control. Despite a long history of extensive use, no resistance or cross-resistance to PVP-I has been recorded, which is in contrast with other antiseptics. Despite previous misconceptions, it has been shown that PVP-I has low allergenic properties, low cytotoxicity and can promote wound healing through increased expression of transforming growth factor beta.
CONCLUSION
With increased understanding of the importance of tackling antimicrobial resistance and bacterial biofilms in acute and chronic wound care, alongside improved understanding of the challenges of antiseptic use, PVP-I remains a promising agent for the management of antisepsis.
Topics: Anti-Infective Agents, Local; Bacteria; Bacterial Infections; Biguanides; Biofilms; Chlorhexidine; Humans; Imines; Povidone-Iodine; Pyridines; Wound Healing
PubMed: 32599228
DOI: 10.1016/j.ijantimicag.2020.106064 -
Nature Communications Mar 2021Effective healing of skin wounds is essential for our survival. Although skin has strong regenerative potential, dysfunctional and disfiguring scars can result from...
Effective healing of skin wounds is essential for our survival. Although skin has strong regenerative potential, dysfunctional and disfiguring scars can result from aberrant wound repair. Skin scarring involves excessive deposition and misalignment of ECM (extracellular matrix), increased cellularity, and chronic inflammation. Transforming growth factor-β (TGFβ) signaling exerts pleiotropic effects on wound healing by regulating cell proliferation, migration, ECM production, and the immune response. Although blocking TGFβ signaling can reduce tissue fibrosis and scarring, systemic inhibition of TGFβ can lead to significant side effects and inhibit wound re-epithelization. In this study, we develop a wound dressing material based on an integrated photo-crosslinking strategy and a microcapsule platform with pulsatile release of TGF-β inhibitor to achieve spatiotemporal specificity for skin wounds. The material enhances skin wound closure while effectively suppressing scar formation in murine skin wounds and large animal preclinical models. Our study presents a strategy for scarless wound repair.
Topics: Animals; Cell Proliferation; Cicatrix; Disease Models, Animal; Extracellular Matrix; Female; Fibroblasts; Hydrogels; Imines; Male; Mice; Rabbits; Signal Transduction; Skin; Sus scrofa; Transforming Growth Factor beta; Wound Healing
PubMed: 33723267
DOI: 10.1038/s41467-021-21964-0 -
Chemical Reviews Jun 2021The merging of click chemistry with discrete photochemical processes has led to the creation of a new class of click reactions, collectively known as photoclick... (Review)
Review
The merging of click chemistry with discrete photochemical processes has led to the creation of a new class of click reactions, collectively known as photoclick chemistry. These light-triggered click reactions allow the synthesis of diverse organic structures in a rapid and precise manner under mild conditions. Because light offers unparalleled spatiotemporal control over the generation of the reactive intermediates, photoclick chemistry has become an indispensable tool for a wide range of spatially addressable applications including surface functionalization, polymer conjugation and cross-linking, and biomolecular labeling in the native cellular environment. Over the past decade, a growing number of photoclick reactions have been developed, especially those based on the 1,3-dipolar cycloadditions and Diels-Alder reactions owing to their excellent reaction kinetics, selectivity, and biocompatibility. This review summarizes the recent advances in the development of photoclick reactions and their applications in chemical biology and materials science. A particular emphasis is placed on the historical contexts and mechanistic insights into each of the selected reactions. The in-depth discussion presented here should stimulate further development of the field, including the design of new photoactivation modalities, the continuous expansion of λ-orthogonal tandem photoclick chemistry, and the innovative use of these unique tools in bioconjugation and nanomaterial synthesis.
Topics: Click Chemistry; Cycloaddition Reaction; Imines; Nitriles; Photochemistry; Tetrazoles
PubMed: 33104332
DOI: 10.1021/acs.chemrev.0c00799 -
Journal of Nanobiotechnology Aug 2023Gene therapy holds great promise for treating a multitude of inherited and acquired diseases by delivering functional genes, comprising DNA or RNA, into targeted cells... (Review)
Review
Gene therapy holds great promise for treating a multitude of inherited and acquired diseases by delivering functional genes, comprising DNA or RNA, into targeted cells or tissues to elicit manipulation of gene expression. However, the clinical implementation of gene therapy remains substantially impeded by the lack of safe and efficient gene delivery vehicles. This review comprehensively outlines the novel fastest-growing and efficient non-viral gene delivery vectors, which include liposomes and lipid nanoparticles (LNPs), highly branched poly(β-amino ester) (HPAE), single-chain cyclic polymer (SCKP), poly(amidoamine) (PAMAM) dendrimers, and polyethyleneimine (PEI). Particularly, we discuss the research progress, potential development directions, and remaining challenges. Additionally, we provide a comprehensive overview of the currently approved non-viral gene therapeutics, as well as ongoing clinical trials. With advances in biomedicine, molecular biology, materials science, non-viral gene vectors play an ever-expanding and noteworthy role in clinical gene therapy.
Topics: Genetic Therapy; Esters; Polyethyleneimine; Polymers; RNA
PubMed: 37592351
DOI: 10.1186/s12951-023-02044-5 -
Molecules (Basel, Switzerland) Oct 2022Many heterocyclic compounds can be synthetized using diaza-1,3-butadienes (DADs) as key structural precursors. Isolated and in situ diaza-1,3-butadienes, produced from... (Review)
Review
Many heterocyclic compounds can be synthetized using diaza-1,3-butadienes (DADs) as key structural precursors. Isolated and in situ diaza-1,3-butadienes, produced from their respective precursors (typically imines and hydrazones) under a variety of conditions, can both react with a wide range of substrates in many kinds of reactions. Most of these reactions discussed here include nucleophilic additions, Michael-type reactions, cycloadditions, Diels-Alder, inverse electron demand Diels-Alder, and aza-Diels-Alder reactions. This review focuses on the reports during the last 10 years employing 1,2-diaza-, 1,3-diaza-, 2,3-diaza-, and 1,4-diaza-1,3-butadienes as intermediates to synthesize heterocycles such as indole, pyrazole, 1,2,3-triazole, imidazoline, pyrimidinone, pyrazoline, -lactam, and imidazolidine, among others. Fused heterocycles, such as quinazoline, isoquinoline, and dihydroquinoxaline derivatives, are also included in the review.
Topics: Butadienes; Hydrazones; Imidazolidines; Imidazolines; Imines; Indoles; Isoquinolines; Lactams; Pyrazoles; Pyrimidinones; Quinazolines; Triazoles
PubMed: 36235245
DOI: 10.3390/molecules27196708 -
Drugs Jun 2023Cipaglucosidase alfa (Pombiliti) is a recombinant human acid α-glucosidase (GAA) product being developed by Amicus Therapeutics along with the enzyme stabilizer... (Review)
Review
Cipaglucosidase alfa (Pombiliti) is a recombinant human acid α-glucosidase (GAA) product being developed by Amicus Therapeutics along with the enzyme stabilizer miglustat as a two-component therapy for Pompe disease. Pompe disease is a rare, inherited lysosomal disease caused by a deficiency of the enzyme GAA, which leads to accumulation of glycogen in various tissues. On 27 March 2023, cipaglucosidase alfa was approved in the EU as a long-term enzyme replacement therapy (ERT) used in combination with miglustat for the treatment of adults with late-onset Pompe disease. This article summarizes the milestones in the development of cipaglucosidase alfa leading to this first approval.
Topics: Adult; Humans; Glycogen Storage Disease Type II; 1-Deoxynojirimycin; Enzyme Replacement Therapy; Glycogen
PubMed: 37184753
DOI: 10.1007/s40265-023-01886-5 -
Trends in Biochemical Sciences Oct 2019Metabolic networks are webs of integrated reactions organized to maximize growth and replication while minimizing the detrimental impact that reactive metabolites can... (Review)
Review
Metabolic networks are webs of integrated reactions organized to maximize growth and replication while minimizing the detrimental impact that reactive metabolites can have on fitness. Enamines and imines, such as 2-aminoacrylate (2AA), are reactive metabolites produced as short-lived intermediates in a number of enzymatic processes. Left unchecked, the inherent reactivity of enamines and imines may perturb the metabolic network. Genetic and biochemical studies have outlined a role for the broadly conserved reactive intermediate deaminase (Rid) (YjgF/YER057c/UK114) protein family, in particular RidA, in catalyzing the hydrolysis of enamines and imines to their ketone product. Herein, we discuss new findings regarding the biological significance of enamine and imine production and outline the importance of RidA in controlling the accumulation of reactive metabolites.
Topics: Amines; Catalysis; Heat-Shock Proteins; Humans; Hydrolysis; Imines; Ketones; Metabolic Networks and Pathways; Ribonucleases
PubMed: 31103411
DOI: 10.1016/j.tibs.2019.04.011 -
Journal of Inorganic Biochemistry Dec 2020With a growing interest in utilizing visible light to drive biocatalytic processes, several light-harvesting units and approaches have been employed to harness the... (Review)
Review
With a growing interest in utilizing visible light to drive biocatalytic processes, several light-harvesting units and approaches have been employed to harness the synthetic potential of heme monooxygenases and carry out selective oxyfunctionalization of a wide range of substrates. While the fields of cytochrome P450 and Ru(II) photochemistry have separately been prolific, it is not until the turn of the 21st century that they converged. Non-covalent and subsequently covalently attached Ru(II) complexes were used to promote rapid intramolecular electron transfer in bacterial P450 enzymes. Photocatalytic activity with Ru(II)-modified P450 enzymes was achieved under reductive conditions with a judicious choice of a sacrificial electron donor. The initial concept of Ru(II)-modified P450 enzymes was further improved using protein engineering, photosensitizer functionalization and was successfully applied to other P450 enzymes. In this review, we wish to present the recent contributions from our group and others in utilizing Ru(II) complexes coupled with P450 enzymes in the broad context of photobiocatalysis, protein assemblies and chemoenzymatic reactions. The merging of chemical catalysts with the synthetic potential of P450 enzymes has led to the development of several chemoenzymatic approaches. Moreover, strained Ru(II) compounds have been shown to selectively inhibit P450 enzymes by releasing aromatic heterocycle containing molecules upon visible light excitation taking advantage of the rapid ligand loss feature in those complexes.
Topics: Biocatalysis; Cytochrome P-450 Enzyme System; Electron Transport; Imines; Ruthenium Compounds
PubMed: 32979791
DOI: 10.1016/j.jinorgbio.2020.111254 -
Molecules (Basel, Switzerland) Jul 2022A number of imines, including 12 new compounds, previously not reported in the literature, derived from variously fluorinated benzaldehydes and different anilines or...
A number of imines, including 12 new compounds, previously not reported in the literature, derived from variously fluorinated benzaldehydes and different anilines or chiral benzylamines were synthesized by a solvent-free mechanochemical method, which was based on the manual grinding of equimolar amounts of the substrates at the room temperature. In a very short reaction time of only 15 min, the method produced the expected products with good-to-excellent yields. The yields were comparable or significantly higher than those reported in the literature for the imines synthesized by other methods. Importantly, the conditions used for the reactions with aniline derivatives also resulted in the high yields of imines obtained from chiral benzylamines, and can be extended to the synthesis with other similar amines. Structures of all imines were confirmed by NMR spectroscopy: H, C and F. For four compounds, X-ray structures were also obtained. The synthetic approach presented in this paper contributes to the prevention of environmental pollution and can be easily extended for larger-scale syntheses. The mechanochemical solvent-free method provides a convenient strategy particularly useful for the preparation of fluorinated imines being versatile intermediates or starting material in the synthesis of drugs and other fine chemicals.
Topics: Amines; Benzaldehydes; Benzylamines; Imines; Magnetic Resonance Spectroscopy
PubMed: 35889430
DOI: 10.3390/molecules27144557