Amyloid ss peptide analogues, oligomers thereof, processes for preparing and compositions comprising said analogues or oligomers, and their uses

An amyloid and analog technology, which can be used in drug combination, compound screening, peptide/protein composition, etc., can solve problems such as increasing heterogeneity and reducing the stability of Aβ globulomers

Inactive Publication Date: 2011-09-28
ABBOTT LAB INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even this approach can lead to formulations that show some degree of heterogeneity when sodium dodecyl sulfate (SDS) is removed and over time
Furthermore, truncations that have been performed for optimal display of globulomer epitopes often further increase heterogeneity and reduce the stability of Aβ globomers
These problems only increase when SDS is removed from the system

Method used

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  • Amyloid ss peptide analogues, oligomers thereof, processes for preparing and compositions comprising said analogues or oligomers, and their uses
  • Amyloid ss peptide analogues, oligomers thereof, processes for preparing and compositions comprising said analogues or oligomers, and their uses
  • Amyloid ss peptide analogues, oligomers thereof, processes for preparing and compositions comprising said analogues or oligomers, and their uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0657] Example 1: Peptide synthesis

[0658] Unless otherwise stated, all reagents were used as obtained from the supplier. Peptide synthesis reagents include diisopropylethylamine (DIEA), N-methylpyrrolidone (NMP), dichloromethane (DCM), (2-(7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethylurea cationic hexafluorophosphate) (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea Cationic hexafluorophosphate (HBTU), 1-hydrobenzotriazole (HOBt) and piperidine were obtained from Applied Biosystems, Inc. (ABI), Foster City, CA; or American Bioanalytical, Natick, MA. Standard 9-fluorenylmethoxycarbonyl (Fmoc) amino acid derivatives (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH, Fmoc-Cys(ACM)-OH, Fmoc-Asp(tBu)-OH, Fmoc- Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Leu-OH, Fmoc -Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr (TBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtaine...

Embodiment 2

[0734] Example 2: Preparation of oligomers

[0735] a) Disulfide bond stabilized (17C, 34C) N-Met Aβ (1-42) oligomer (2a)

[0736] 83.1 mg of synthetic (17C, 34C) N-Met Aβ(1-42) (1a), TFA salt, (1 ml for every 6 mg peptide) of Example 1a was treated with HFIP, and the solvent was removed by lyophilization. Dissolve this in 4.0 ml DMSO. Then with stirring, this DMSO solution of the peptide was slowly added to 45 mL of 20 mM PBS (20 mM NaH) containing 0.2% SDS (sodium dodecyl sulfate) 2 PO 4 , 140 mM NaCl, pH 7.4). This solution was then made 5 mM in DTT (dithiothreitol) and incubated at 37°C for 6 hours.

[0737] The sample was then diluted with 3 parts of water and dialyzed against quarter-strength PBS containing 0.05% SDS overnight at room temperature using a 3500 MWCO dialysis membrane. The next morning, dialysis was continued for 2 hours against 1 L of fresh buffer at 4°C.

[0738] The YM10 membrane was then used to concentrate the sample in an Amicon stirred cell. A 0.5 ml ali...

Embodiment 3

[0739] Example 3: Preparation of oligomers

[0740] a) (14C, 37C) N-Met Aβ (1-42) oligomer (3a)

[0741] The (14C, 37C) N-Met A? (1-42) peptide (1b) of Example 1b was suspended in 100% 1,1,1,3,3,3-hexafluoro-2- Propanol (HFIP) and incubate at 37°C for 2 hours with shaking for complete dissolution. HFIP acts as a hydrogen bond disruptor and is used to eliminate pre-existing structural inhomogeneities in Aβ peptides. HFIP was removed by evaporation in SpeedVac, and Aβ peptide was dissolved or suspended in dimethyl sulfoxide at a concentration of 5 mM, and sonicated for 20 seconds. Use 230 μl phosphate buffered saline (PBS) + 0.2% SDS + 2 mM DTT (in H 2 O + 3 mg DTT dissolved in 9.8 ml helium aerated 20 mM NaH 2 PO 4 , 140 mM NaCl, pH 7.4 + 0.2 ml 10% SDS solution, Serva, catalog number: 20710), dilute 20 μl HFIP pretreated Aβ peptide in DMSO to a peptide concentration of 400 μM. Incubation at 37°C for 6 hours resulted in 16 / 20-kDa (xC, yC) N-Met Aβ(1-42) intermediate and Aβ(1-42) ...

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Abstract

The present invention relates to relates to an amyloid ss peptide analogues comprising an amino acid sequence or a peptidomimetic thereof, wherein the sequence (i) forms a loop, (ii) has at least 66 % identity to the amino acid sequence of native Ass peptide or a portion thereof, (iii) comprises at least 6 contiguous amino acid residues and (iv) has at least 2 non-contiguous amino acid residues which are covalently linked with each other, oligomers comprising a plurality of said amyloid ss peptide analogues, processes for preparing the amyloid ss peptide analogues or oligomers, compositions comprising the amyloid ss peptide analogues or oligomers, and uses of the amyloid ss peptide analogues or oligomers such as their use for treating or preventing an amyloidosis (e.g.; by active immunization), for diagnosing an amyloidosis, and for providing agents that are capable of binding to the amyloid ss peptide analogues or oligomers. The subject invention also describes agents that are capable of binding to the amyloid ss peptide analogues or oligomers, e.g. antibodies, compositions comprising the agents, and uses of the agents such as their use for treating or preventing an amyloidosis (e.g. by passive immunization) and for diagnosing an amyloidosis.

Description

Invention field [0001] The present invention relates to amyloid β peptide analogs, including a plurality of oligomers of the amyloid β peptide analogs, and a method for preparing amyloid β peptide analogs or oligomers, including amyloid β The composition of peptide analogs or oligomers, and the use of amyloid beta peptide analogs or oligomers, for example, for the treatment or prevention of amyloidosis (for example, by automatic immunization), for the diagnosis of amyloid Denaturation and use for providing reagents capable of binding to amyloid beta peptide analogs or oligomers. The present invention also describes reagents capable of binding to amyloid β peptide analogs or oligomers, such as antibodies, compositions comprising reagents, and uses of reagents, such as their use in the treatment or prevention of amyloidosis (for example, by Passive immunization), and for the diagnosis of amyloidosis. Background of the invention [0002] In 1907, Dr. Alois Alzheimer first describe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17C07K14/47C07K16/18G01N33/68
CPCG01N2500/04C07K2319/00C07K14/4711G01N2333/4709A61K38/00C07K16/18G01N2800/2821A61P25/28
Inventor S·巴霍恩H·希伦R·埃达尔吉L·巴雷特P·理查森郁立平E·奥勒尼查克J·哈兰T·霍尔斯曼
Owner ABBOTT LAB INC
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