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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
Interestingly, by following a similar strategy starting from N-butylglucamine 119, it was possible to produce Miglustat (N-butyl-deoxynojirimycin 120, Fig. 11.41, marketed as Zavesca™), another glycosidase inhibitor acting as a pharmacological chaperone for brain glucosylceramide synthase, therefore avoiding the accumulation of glucosylceramide leading to Gaucher’s disease (Yu et al., 2007). Synthesis of Miglustat 120 via regioselective biooxidation of N-butylglucamine 119.
Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies
Published in Expert Opinion on Drug Safety, 2021
Mina Tsurumi, Shinya Suzuki, Jiro Hokugo, Kazuo Ueda
The number of therapies available for patients with lysosomal storage diseases has expanded considerably in the past several years [15,16]. Enzyme replacement therapy (ERT) represents the mainstay of treatment for Fabry Disease, with two different human recombinant α-GAL ERTs developed for Fabry disease. Agalsidase beta (Fabrazyme®), a recombinant form of human α-GAL, has been approved for the treatment of Fabry disease in the European Union and United States since 2001 [17] and 2003 [18], respectively, and in Japan since 2004 [19]. The other ERT, agalsidase alfa, has been available in the European Union since 2001 [20] and Japan since 2006 [21]. Administration of these agents has been shown to result in marked increases in α-GAL A activity in human Fabry cells and Fabry mouse tissues; however, enzymatic activity in cultured fibroblasts, kidneys, heart, and spleen was higher for agalsidase beta compared with agalsidase alfa [22]. More recently, pharmacological chaperone therapies have become available, and substrate reduction therapies and gene therapy approaches are also in development, which are expected to improve outcomes for patients with Fabry disease [23].
Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.
Published in Expert Opinion on Therapeutic Targets, 2019
John W. Hanrahan, Yukiko Sato, Graeme W. Carlile, Gregor Jansen, Jason C. Young, David Y. Thomas
This class of proteostasis modulators augments the total amount of F508del-CFTR that is available for folding [55]. PYR-41, an E1 ubiquitin activating enzyme inhibitor provides a proof of principle for the amplifier mechanism of correction. It increases the amount of immature F508del-CFTR by blocking an early step in proteasomal degradation and synergistically enhances subsequent rescue by a pharmacological chaperone [56]. This approach has been further validated for a deletion mutant lacking 6 residues in NBD2 (ΔI1234_R1239‐CFTR), which responds more robustly to orkambi when its expression is elevated by the amplifier PTI-CH [57]. Many hits from corrector screens may act in part through such increases in the amount of F508del-CFTR protein available for rescue by increasing CFTR transcription and translation and/or by inhibiting ER associated degradation (ERAD).
Tryptophan hydroxylase 2 as a therapeutic target for psychiatric disorders: focus on animal models
Published in Expert Opinion on Therapeutic Targets, 2019
Elizabeth A. Kulikova, Alexander V. Kulikov
The last decade particular attention is paid to pharmacological chaperons (Figure 3). They are low-weight molecules that rescue misfolded conformations of enzymes and thereby correct their activity [78]. Some mutations in the oligomerization domain of tryptophan hydroxylases, tyrosine and phenylalanine hydroxylases can violate the enzymes folding, structures and thereby activities [79,80]. One of the natural pharmacological chaperones common for all L-aromatic amino acid hydroxylases is BH4 (Figure 3). These chaperones were tested mainly on phenylalanine hydroxylase [80,81] which is similar in structure to TPH2 [33]. A potential pharmacological chaperone for TPH2, 3-amino-2-benzyl-7-nitro-4-(2-quinolyl)-1,2-dihydroisoquinolin-1-one (Figure 3) improves thermal stability and increases the TPH2 activity in vitro [79]. At the same time, there is no information about effects of this compound (or its derivatives) on the TPH2 activity in vivo.