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New use of ebselen

A technology of ebselen and its use, which is applied in the field of drugs for the treatment of type I mucopolysaccharidosis, and can solve the problems of expensive treatment and high cost

Active Publication Date: 2021-07-16
上海兴糖生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, due to the high cost of enzyme production, the treatment is very expensive and unaffordable for ordinary families.
Therefore, there is an unmet clinical need to develop cheaper and easy-to-use drugs for all MPS-I patients

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Ebselen inhibits the activity of GAG synthesis epimerases HS-epi and DS-epi1

[0039] Enzyme activity test:

[0040] DS-epi1 activity in 100 μl buffer (20mM MES, pH 5.5, 10% glycerol, 2mMMnCl 2 ), using 30000dpm substrate [5- 3 H]dK4 (substrate prepared according to (Hannesson, H.H., A. Hagner-McWhirter, K. Tiedemann, U. Lindahl, and A. Malmstrom. 1996. Biochem J, 313 (Pt 2): 589-96.), test Method adapted from (Maccarana, M., B. Olander, J. Malmstrom, K. Tiedemann, R. Aebersold, U. Lindahl, J.P. Li, and A. Malmstrom. 2006. J Biol Chem. 281:11560-8.) ). After incubation at 37°C for 16-20 hours, 90 μl of the mixture was added to a scintillation vial (Campbell, P. ., H.H. Hannesson, D. Sandback, L. Roden, U. Lindahl, and J.P. Li. 1994. J Biol Chem. 269:26953-8). Vials were spun down for 30 seconds and equilibrated for at least 6 hours prior to scintillation counting of radioactivity. Background≤200dpm.

[0041] The activity of HS-epi was tested in 50μl co...

Embodiment 2

[0048] Example 2: Effect of ebselen on MPS-I fibroblast synthesis and catabolism of GAG in vitro

[0049] Cell culture:

[0050]Primary human dermal fibroblasts derived from a 1-year-old MPS-I patient and a healthy age-matched donor were purchased from the “Cell Lines and DNA Biobank from Patients Affected by Genetic Diseases” (Genova, Italy Gaslini Institute). MPS-I fibroblasts have the stop codon pW402X in the iduronidase gene, the most common MPS-I variant for this mutation (31% worldwide) (Kubaski, F., F.de et al . 2020. Diagnostics (Basel), 10.). Detection of fibroblast lysates (Ou, L., T.L. Herzog, C.M. Wilmot, and C.B. Whitley. 2014) with the fluorogenic substrate 4-methylumbelliferyl-α-L-idosyl (Ou et al. 2014) .Mol Genet Metab, 111:113-5.) showed that the iduronidase activity was significantly reduced (5000 times less in pW402X MPS-I fibroblasts than in control fibroblasts). Fibroblasts were cultured in DMEM, 10% fetal bovine serum (FBS), 100 units / ml penicillin a...

Embodiment 3

[0062] Example 3: Effects of Ebselen on Xenopus Embryo Development in Vivo

[0063] Xenopus embryo manipulation experiments:

[0064] For in vivo pharmacological inhibitory treatment, embryos were cultured from the neurula stage (stage14 or st. Incubate in saline (MBS) at 17°C, add 0.025% dimethyl sulfoxide (DMSO) alone as a control group, or add 12.5 μM ebselen together as a drug administration group. Embryos were prepared, cultured, and Lineage tracing and in situ hybridization by Red-Gal staining.

[0065] Antisense morpholino oligonucleotide (Dse-MO) (5′-GCT CCC CGA GTG TGA GTC CTC ATT G-3′, SEQ ID No.: 1) and standard control-MO (5′-CCT CTT ACC TCA GTT ACA ATT TAT A-3', SEQ ID No.: 2) was purchased from Gene Tools LLC. For synthesis of nlacZ mRNA, pCS2-nlacZ cDNA was linearized with NotI using the mMessage Machine kit (Ambion) and transcribed with Sp6 RNA polymerase. Morpholino (MO) animals were injected into all blastomeres at the two or four cell stage unless other...

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PUM

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Abstract

The invention relates to a new use of ebselen, and specifically relates to a use of ebselen and a pharmaceutical composition thereof in preparation of a medicine for treating type I mucopolysaccharide storage diseases.

Description

technical field [0001] The invention belongs to the field of medicine, in particular, the invention relates to the use of ebselen in the preparation of medicines for treating type I mucopolysaccharidosis. Background technique [0002] Mucopolysaccharides, also known as glycosaminoglycans (GAG for short), are long-chain acidic polysaccharide compounds composed of hexuronic acid and hexosamine repeating disaccharide units widely distributed in various tissues of mammals, including chondroitin sulfate ( Chondroitin Sulfate, CS), dermatan sulfate (Dermatan Sulfate, DS), and heparan sulfate (Heparan Sulfate, HS), etc. GAG usually exists widely on the cell surface and extracellular matrix in the form of proteoglycans by covalently binding core proteins, and is mainly responsible for the correct structure and function of connective tissue, and often acts as a co-receptor by binding growth factors, cytokines, etc. Participate in the communication between cells, help different subst...

Claims

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Application Information

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IPC IPC(8): A61K31/41A61P43/00
CPCA61K31/41A61P43/00
Inventor 方建平马克·麦卡拉纳李晋萍
Owner 上海兴糖生物技术有限公司
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