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Methods for treating protein aggregation disorders

A technology for protein aggregation and disease, which is applied to nervous system diseases, pharmaceutical formulations, medical preparations containing active ingredients, etc., and can solve problems such as no disease treatment drug treatment methods

Inactive Publication Date: 2006-09-27
NEUROCHEM INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, there are no therapeutic drugs and fully effective treatments for these diseases

Method used

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  • Methods for treating protein aggregation disorders
  • Methods for treating protein aggregation disorders
  • Methods for treating protein aggregation disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0513] Embodiment 1: to detect the protein aggregation disease-related

[0514] Assay for harmful protein aggregates

[0515] Assay to detect deleterious protein aggregates associated with deleterious accumulation of NAC

[0516] Preparation of NAC peptide

[0517] As discussed herein, the acronym NAC refers to the non-amyloid component of amyloid plaques found in AD patients, specifically, residues 61-95 corresponding to α-synuclein of 35 amino acid peptides. NAC peptide was synthesized by Fmoc tert-butyl chemistry on a peptide synthesizer from Protein Technologies, Inc. with a purity of >98%. The peptide content was determined to be 71.6% by amino acid analysis.

[0518] Preparations of NAC may contain aggregated material. To remove these aggregates and monomerize the peptides, a lower deaggregation / filtration method was obtained adapted from the article by Walsh and Colleagues (J Biol Chem. 1997 Aug 29;272(35):22364-72). This method involves so...

Embodiment 2

[0528] Example 2: Application of Thioflavin T Assay in Determining Formation of β-Sheets by Isolated NAC

[0529] Trials that have been performed have shown that Thioflavin T (ThT) can be used in high-throughput and validation work using NAC peptides. A fluorescent signal indicating β-sheet formation begins to appear after 10 hours of incubation ( figure 1 ). The intensity of the fluorescent signal is directly related to the concentration of NAC in solution, reaching a maximum at 30 μM NAC. (in 96-well plate) observed T 1 / 2 (Time required to obtain a signal equal to half the maximum signal obtained) was ~15 hours for a similar ThT profile.

Embodiment 3

[0530] Example 3: Circular Dichroism Analysis and Electron Microscopy Analysis of NAC Peptide Conformation

[0531] Circular dichroism analysis of the conformation of the NAC peptide after incubation for 10-72 h (Fig. 2) revealed a minimum at 227 nm, reminiscent of that observed in regions rich in α-helices . After incubation of NAC in the presence of heparin, its CD spectrum showed a distinct minimum at 218 nm, which is characteristic of the β-sheet conformation. Electron microscopic analysis (Fig. 3) detected the appearance of NAC fibers. The presence of heparin clearly promotes a conformational transition and favors a high β-sheet content that promotes aggregate / fibril formation (Figure 2). This result indicates that glycosaminoglycans are indeed involved in the oligomerization / fibril formation process of NAC, confirming the effectiveness of the approach of using GAG mimetic compounds as a means to prevent NAC oligomerization and formation of toxic aggregates. EM ana...

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PUM

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Abstract

The present invention is based, at least in part on the discovery of therapeutic agents capable of preventing, inhibiting or modulating abnormal processing, misfolding or aggregation of protein. The therapeutic agents of the invention may prevent, inhibit or modulate the formation of inclusions. The therapeutic agents of the invention may also be capable of facilitating clearance and / or blocking the cellular toxicity of inclusions to treat or ameliorate disorders characterized by protein aggregation. Compounds which bind to structural motifs commonly found in protein aggregates, such as ss-sheets, would represent strong candidates for such compounds and are therefore desirable.

Description

[0001] related application [0002] This application claims the benefits of U.S. Provisional Patent Application 60 / 480,918, filed June 23, 2003, U.S. Provisional Application 60 / 512,017, filed October 17, 2003, and U.S. Application 10 / ____,____, filed June 18, 2004 Priority, the titles of the above three applications are "Methods for Treating Protein Aggregation Disorders" (Methods for Treating Protein Aggregation Disorders). [0003] This application is related to U.S. Provisional Patent Application 60 / 480,984, filed June 23, 2003, U.S. Provisional Patent Application 60 / 512,116, filed October 17, 2003, and U.S. Application 10 / ____,____, filed June 18, 2004 (Docket No. NBI-152), entitled "Pharmaceutical Formulations of Amyloid-Inhibiting Compounds." [0004] This application is related to U.S. Provisional Application 60 / 482,214, filed June 23, 2003, and U.S. Provisional Application 60 / 436,379, filed December 24, 2002, entitled "Combination Therapy for Alzheim...

Claims

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Application Information

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IPC IPC(8): A61K31/185A61K31/445A61K31/495A61P25/00A61P25/16A61P25/28
Inventor P·特伦布莱R·麦克劳克林
Owner NEUROCHEM INT
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