China
Africa
Explore chapters and articles related to this topic
Infiltrative Cardiomyopathies
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Arthur Qi, Quynh Nguyen, Haran Yogasundaram, Gavin Y. Oudit
Substrate reduction therapy, specifically eliglustat tartrate (Genz-112638), is an emerging treatment for FD, and represents an alternative approach to reducing glycosphingolipid levels that has proven effective in treating Gaucher disease, another glycosphingolipidosis.34 Through inhibition of the glucosylceramide synthase enzyme that catalyzes the first step of glycosphingolipid synthesis, substrate reduction therapy reduces upstream production of glycosphingolipids.23 In FD mouse models, substrate reduction therapy has been shown to reduce Gb3 and lyso-Gb3 levels in the kidneys, heart, and liver, with maximal effect when used in conjunction with ERT.23,27 However, eliglustat was ineffective at lowering glycosphingolipid levels in the brain due to its poor ability to cross the blood-brain barrier.35 A novel oral glucosylceramide synthase inhibitor, ibiglustat (Genz-682452), was designed to cross the blood brain barrier and has shown efficacy in lowering Gb3 and lyso-Gb3 levels in the brain, especially in conjunction with ERT.34
Gaucher disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Another approach, called substrate reduction therapy, is possible with an inhibitor of ceramide glucosyltransferase, and the agent N-butyldeoxynojirimycin was approved in 2004 (miglustat) for adult patients with Gaucher disease for whom IV enzyme replacement is not practical [90–92]. Results are similar to those [93] with enzyme therapy [19]. Studies are underway using a more specific glucosylceramide synthase inhibitor, eliglustat tartrate [94].
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.
Current and emerging pharmacotherapy for Gaucher disease in pediatric populations
Published in Expert Opinion on Pharmacotherapy, 2021
Richard Sam, Emory Ryan, Emily Daykin, Ellen Sidransky
Substrate reduction therapy targeting pathways that produce glucocerebroside was first approved by the Food and Drug Administration (FDA) to treat GD in 2003 [88,89]. Developed using glucosylceramide synthase inhibitors, SRT treatment aims to reduce accumulating glycosphingolipids. The two currently approved oral SRTs for the treatment of GD, miglustat and eliglustat tartrate, are intended exclusively for adult patients with GD1 (Table 2) [90,91]. Compared to intravenously administered ERT, the orally taken SRT rapidly diffuses into various tissues and has the potential advantage of improving bone complications through direct drug delivery to bone compartments. A recent study assessed the possible use of RANK pathway components, major effectors at multiple levels of the bone regeneration cycle, as markers for bone disease progression in GD [92]. Here, they reported a reduction in osteoclastogenic biomarkers in a cohort of patients on SRT compared to an ERT cohort. While further evidence is required, the probable reduction in osteoclast activity with SRT suggests that this therapy might be useful in treating patients with specific bone complications [92].
Novel approaches to glycomimetic design: development of small molecular weight lectin antagonists
Published in Expert Opinion on Drug Discovery, 2021
Vishnu C. Damalanka, Amarendar Reddy Maddirala, James W. Janetka
This review provides an overview of the various approaches which have been used during the last 10–15 years in rationally designing small molecular weight glycoside ligands of lectins as glycomimetics of their carbohydrate-binding partners. In this manuscript, we have limited the scope to those lectins and lectin classes (Table 1) that are most promising in drug discovery and development. The medicinal chemistry and rational drug design of selected mammalian and non-mammalian lectin antagonists are discussed in the following sections. Shown in Figure 1 are the structures of a few selected glycomimetic drug molecules that have successfully completed clinical trials which do not target lectins but are drugs now approved by the FDA for influenza A and B viral infections (Neuraminidase inhibitors; Relenza and Tamiflu) [33,34], Gaucher disease (Glucosylceramide synthase inhibitor; Zavesca) [35] and type 2 diabetes (α-Glucosidase inhibitors; Glyset; Voglib; and Glucobay) and Sodium-GLucose Transport protein 2 (SGLT2) inhibitors; Farxiga, Lusefi; and Zynquista [36–39].
The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain
Published in Expert Opinion on Therapeutic Targets, 2020
Michiel Langeslag, Michaela Kress
Ceramide and other sphingolipid metabolites derived from ceramide, like sphingosine-1-phosphate (S1P) and lactosylceramide (LacCer) have important pathophysiological functions, mainly in inflammatory-related diseases and inflammatory responses [7]. Secretion of pro-inflammatory cytokines by immune cells activate the conversion of sphingomyelin into ceramide by sphingomyelin phosphodiesterase isoenzymes (SMPDs). Ceramide can be converted to glucosylceramide (glucosylceramide synthase) which acts as a substrate for lactosylceramide synthase (LCS) to produce LacCer Figure 1. On the one hand, S1P can be generated from ceramide through conversion to sphingosine by ceramidases and subsequent phosphorylation by sphingosine kinases (SPHK1, SPHK2), which forms the rate limiting step in S1P production. S1P has potential intracellular actions [8,9]. Normally, intracellular S1P levels are remained low by either dephosphorylation of S1P by sphingosine phosphatase or irreversible degradation by S1P lyases [10]. S1P with its polar headgroup connected to hydrophobic acyl chain can act as diffusible, intercellular signaling molecule through secretion from cells. The most widely studied S1P transporter is SPNS2, S1P-mediated transport is increased after overexpression of SNPS2. Reversely, down-regulation of SPNS2 decreases S1P release [11–13]. In addition to S1P, SPNS2 can also transport S1P analogs like FTY720-P [11,13]. Also, other transporters for S1P exist such as ABCA1 [14], ABCC1 [15–18], ABCG2 [17] and the recently discovered Mfsd2b [19,20]. Mfsd2b has been identified in erythrocytes and platelets and belongs to the family of transporters as SPNS2.