Compositions for treating and/or preventing protein-aggregation diseases

A protein aggregation and composition technology, which can be used in drug combinations, nervous system diseases, active ingredients of heterocyclic compounds, etc., can solve the problem of not further increasing the lifespan of sul-2 deletion mutants

Pending Publication Date: 2021-04-02
帕布罗德奥拉韦德大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, STX64 did not further increase the lifespan of sul-2 deletion mutants, suggesting that the mechanism by which STX64 increases lifespan is through inhibition of the sulfatase activity of SUL-2 (WO 2014 / 154927A1)

Method used

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  • Compositions for treating and/or preventing protein-aggregation diseases
  • Compositions for treating and/or preventing protein-aggregation diseases
  • Compositions for treating and/or preventing protein-aggregation diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Example 1: Effects of STX64 on nematode models of neurodegenerative diseases

[0118] Caenorhabditis elegans model of Parkinson's disease: We tested whether sul-2 mutation or treatment with STX64 (Sigma cat# S1950) dissolved in DMSO at a concentration of 1 μg / ml improved human α-synuclein in muscle cells Symptoms due to overexpression (see the following references for information on the models used: van Ham et al., 2008.PLoS Genet.4(3):e1000027; Gidalevitz et al., 2009.PLoS Genet.5(3):e1000399; van Ham et al. Ham et al., 2010. Cell. 142(4):601-12). In particular, nematodes were synchronized at 20 °C and monitored every two days. On each day of monitoring, nematodes were placed in a drop of M9 buffer, adapted for 30 seconds, and then the number of swings in 1 min was counted, assuming that a swing occurred when the head of the nematode passed through the axial shaft. Assays and conditions were performed daily for N=20 (the protocol was adapted from Van Ham et al., 2010...

Embodiment 2

[0123] Example 2: Effects of STX64 on Mammalian Models of Neurodegenerative Diseases

[0124] Mouse strains and conditions: Male Swiss (CD1) and APP-PS1 (Blanchard et al., 2003. Exp Neurol. 184(1):247-63) mice used in this study were purchased from authorized providers ( University of Seville, Spain), and acclimatized them to standard animal housing conditions for 2 to 3 weeks (12-h light / dark cycle, temperature and humidity). Behavioral studies were performed with 8-week-old Swiss mice and APP-PS1 mice older than 15 months on a C57Black background. For histological studies, male APP-PS1 mice from 2 to >15 months of age were used. All experiments were carried out in accordance with EU guidelines (2010 / 63 / EU) and Spanish regulations on the use of laboratory animals in chronic experiments (RD 53 / 2013 on the care of laboratory animals: BOE 08 / 02 / 2013) and the study was carried out Approval was previously obtained from the Pablo de Olavide University Animal Care Committee.

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Embodiment 3

[0132] Example 3: Effect of STX64 on Huntington's disease mouse model

[0133] Mouse strains and conditions: R6 / 1 mice used in this study (Yi Li et al., 2005.NeuroRX.2(3):447-464; Mangiarini et al., 1996.Cell.87(3): 493-506) were purchased from authorized providers and they were acclimated to standard animal housing conditions for 2 to 3 weeks (12 hour light / dark cycle, temperature and humidity). Locomotor activity studies were performed with 2-month-old R6 / 1 mice. All experiments were performed in accordance with EU guidelines (2010 / 63 / EU) and Spanish regulations on the use of laboratory animals in chronic experiments (RD 53 / 2013 on the care of laboratory animals: BOE08 / 02 / 2013) and before conducting the study Approval was obtained from the Pablo de Olavide University Animal Care Committee.

[0134] Oral administration of STX to mice: Dissolve STX64 in drinking water at 0.005mg / ml. One-month-old mice were exposed to the STX solution for 1 month, and water intake was record...

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Abstract

Proteopathies cover a wide spectrum of afflictions, including neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, polyglutamine diseasessuch as Huntingtin in Huntington's disease, prion diseases); amyloidosis of other non-nervous system proteins such as 1-antitrypsin, immunoglobulin light and heavy chains, lactadherin, apolipoprotein, gelsolin, lysozyme, fibrinogen, atrial natriuretic factor, keratin, lactoferrin and beta-2 microglobulin, among others); sickle cell disease; cataracts; cystic fibrosis; retinitis pigmentosa; and nephrogenic diabetes insipidus.Surprisingly, the administration of a sulfatase inhibitor is suitableto treat and / or prevent the proteotoxicity commonly associated with proteopathies. The present invention, therefore, provides compositions comprising sulfataseinhibitors for the treatment of proteopathies.

Description

technical field [0001] The present invention is included in the field of medicine and provides compositions for treating and / or preventing protein aggregation diseases. Background technique [0002] The proper functioning of organs and cells within an organism depends on the proper function of proteins. A protein is a biological entity that has the following: primary amino acid sequence; secondary structure, which forms protein domains and, most importantly, includes alpha helices and beta sheets; tertiary structure, which is the complex folding of peptide chains in three dimensions As a result, this outcome involves interactions between the polypeptide chain backbone and the amino acid side chains. Some proteins function in multisubunit complexes, where the arrangement of multiple proteins into a quaternary structure is critical for their proper function. [0003] The inability of proteins to fold into their correct three-dimensional structure can lead to diseases known a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/37A61K45/06A61P25/16A61P25/28A61P43/00
CPCA61K31/37A61K45/06A61P25/16A61P25/28A61P43/00A61K31/13A61K31/198A61K31/27A61K31/445A61K31/55
Inventor 曼纽尔·J·穆诺兹安吉尔·M·卡里安梅赛德斯·M·佩雷斯-吉美内兹
Owner 帕布罗德奥拉韦德大学
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