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Infiltrative Cardiomyopathies
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Arthur Qi, Quynh Nguyen, Haran Yogasundaram, Gavin Y. Oudit
More recently, the iminosugar 1-deoxygalactonojirimycin (migalastat hydrochloride) has been approved for treatment of FD. It functions as a pharmacological chaperone and potent inhibitor of α-Gal A that binds the active site of the enzyme and improves its folding, stability, and lysosomal trafficking, after which it dissociates to allow an α-Gal A to catalyze the degradation of Gb3.31–33 Migalastat has been shown to cause durable increase in α-Gal A activity and significant reduction in glycosphingolipid levels in lysates from the kidneys, heart, and liver.31,32 Migalastat presents several advantages over ERT: its ability to cross the blood-brain barrier, oral rather than intravenous route of administration, and higher volume of distribution, which may enhance α-Gal A levels in multiple organs.26,33 However, migalastat only improves the stability and activity of α-Gal A in patients with amenable missense mutations causing misfolding of α-Gal A, 78 of which have been identified to date.31,32 Therefore, many nonsense and missense mutations resulting in both classic and variant phenotypes are not amenable to this treatment.
Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
It is well known that inhibitors of intestinal α-glucosidase enzymes promote a delay in the absorption of sugars because of the retard in the final steps of carbohydrate digestion, so that they are useful for reducing postprandial hyperglycemia in diabetes (Derosa and Maffioli, 2012; Campo et al., 2013). These α-glucosidase inhibitors act as glycomimetics, because they bear a certain grade of resemblance to the natural carbohydrates, but the differential part of their structure promotes a blockade of enzymatic action (Ernst and Magnani, 2009). The use of iminosugars (N atom replacing O) (Winchester, 2009; Horne et al., 2011), thiosugars (S instead of O) (Witczak and Culhane, 2005) or carbasugars (ethereal bridge substituted by a methylene) (Mayato et al., 2012) as glycomimetics is a well-developed strategy. More specifically, iminosugars mimics transition state (oxocarbenium) of glycosidases mechanism, due to the nitrogen protonation at physiological pH values (Caines et al., 2007; Winchester, 2009), and we will show some examples of biocatalyzed synthesis of this type of α-glucosidase inhibitors.
Functional Foods Continued
Published in Robert Fried, Richard M. Carlton, Type 2 Diabetes, 2018
Robert Fried, Richard M. Carlton
The International Journal of Toxicology reports that M. alba leaves and their constituents, particularly iminosugars (or azasugars), have gained interest for their ability to maintain normal blood glucose concentrations. Reducose (Phynova Group Limited) is a patented commercial water-soluble extract of M. alba leaves standardized to 5% DNJ, an iminosugar with α-glucosidase inhibition properties.
Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
I. Caroline Vaaland, Óscar López, Adrián Puerta, Miguel X. Fernandes, José M. Padrón, José G. Fernández-Bolaños, Magne O. Sydnes, Emil Lindbäck
Iminosugars are glycomimetics in which the ring oxygen atom has been replaced by a nitrogen atom17. Iminosugars are attractive as pharmaceutical candidates because they inhibit glycosidases without being metabolised by such enzymes18. Such properties have made iminosugars attractive as synthetic targets19 and lead compounds for the treatment of various diseases such as viral infections, diabetes, type 2 diabetes, and lysosomal disorders20. In addition, it has been found that iminosugars are able to inhibit the growth of cancer cells21,22, without affecting the viability and mortality of normal cells21. To date, three iminosugars, namely, miglitol23, miglustat24, and migalastat25 have been approved by FDA for the treatment of type 2 diabetes, Gaucher’s disease, and Fabry’s disease, respectively. Miglustat has also been found to reduce the production of amyloid β-peptide (Aβ)26, which is a component of senile plaque in AD patients.
A hybrid of 1-deoxynojirimycin and benzotriazole induces preferential inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Tereza Cristina Santos Evangelista, Óscar López, Adrián Puerta, Miguel X. Fernandes, Sabrina Baptista Ferreira, José M. Padrón, José G. Fernández-Bolaños, Magne O. Sydnes, Emil Lindbäck
Iminosugars, such as naturally occurring 1-deoxynojirimycin (1-DNJ) (4) (Figure 1(b)) are carbohydrate analogues in which the ring oxygen atom is replaced by a nitrogen atom. Many iminosugars can be partially protonated at physiological pH, in which the conjugate acid can be considered as a charged analogue of the transition state of glycosidase catalysed cleavage of glycosidic bonds.11 Therefore, it is not surprising that iminosugars are mostly famous for their properties as glycosidase inhibitors.12 The glycosidase inhibitory properties of iminosugars have made them attractive as lead compounds for treatment of diseases such as cancer, diabetes, viral infections, and lysosomal disorders in which carbohydrate processing enzymes are apparent pharmaceutical targets.13 The FDA has approved three iminosugars: miglitol (5),14 miglustat (6),15 and migalastat (7)16 for treatment of type 2 diabetes, Gaucher’s disease, and Fabry’s disease, respectively. In addition, in a cellular model of H4APPsw it has been found that miglustat (6) lowers the level of Aβ protein,17 which is the major component in senile plaque.
New avenues for therapeutic discovery against West Nile virus
Published in Expert Opinion on Drug Discovery, 2020
Alessandro Sinigaglia, Elektra Peta, Silvia Riccetti, Luisa Barzon
Since flaviviruses have crucial interactions with the host ER for genome replication, ER-associated proteins can be important drug targets [171,172]. Genome-wide CRISPR screening identified (ER)-membrane multiprotein complexes, including the oligosaccharyltransferase (OST) complex, as critical flavivirus host factors [171]. Actually, NGI-1, a small-molecule inhibitor of ER-associated OST, caused an impressive suppression of RNA replication in vitro of several flaviviruses, including ZIKV, DENV, YFV, and WNV, with a mechanism independent of inhibition of the N-glycosylation function of the OST [173]. Another ER group of proteins, α-glucosidases, were shown to be relevant for virion assembly. Their inhibition with iminosugar derivatives led to in vitro and in vivo antiviral effects against enveloped viruses, including flaviviruses, HCV, and influenza virus [174,175]. Among candidate iminosugar derivatives, the prodrug celgosivir demonstrated high antiviral activity in vitro and in vivo [176–178]. However, a randomized phase I proof-of-concept clinical trial did not show any benefit of celgosivir in reducing viral load or fever in patients with dengue fever [179].