Secondary structural modifications of Aβ(1–40) induced by multiple 2-acetoxy-4-methoxybenzyl (acetylHmb) protection

Clippingdale, Andrew B.; He, Weilan; Macris, Mary; Wade, John D.; Barrow, Colin J.

doi:10.1007/bf02443424

Cited by 3 publications

(6 citation statements)

References 17 publications

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“…Similar difficulties are encountered using neutral pH reversed phase chromatography though better profiles are obtained when chromatography is performed under basic conditions, likely due to enhanced peptide solubility [37]. As alternative chemical approaches, researchers have explored the use of O-N intramolecular acyl migration in Aβ isopeptides [36,[38][39][40], as well as novel protection strategies for preparing the peptide in soluble form [32,33,35,41]. The isopeptide approach employs the well established O-N acyl migration reaction which occurs in Ser/Thr containing peptides [38].…”

Section: Addl Preparation and Isolationmentioning

confidence: 95%

“…Synthetic peptide preparation of Aβ1-42, Aβ1-40, and fragments thereof, have provided an alternate source of these reagents [reviewed in 29]. However, the inherent hydrophobicity of these peptides coupled with their intrinsic propensity to aggregate in a variety of media has presented considerable synthetic challenges [30][31][32][33][34][35]. While solid phase synthesis via standard Fmoc and T-Boc routes has been achieved, subsequent purification of the peptides using standard acetonitrile/water/TFA HPLC conditions has generally been difficult due to broad elution patterns [36].…”

Section: Addl Preparation and Isolationmentioning

confidence: 99%

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The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimers Disease

Catalano

Dodson²,

Henze³

et al. 2006

CTMC

102

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The amyloid-beta (Abeta) cascade hypothesis of Alzheimer's disease (AD) has dominated research and subsequent therapeutic drug development for over two decades. Central to this hypothesis is the observation that Abeta is elevated in AD patients and that the disease is ultimately characterized by the central deposition of insoluble senile plaques. More recent evidence, however, suggests that the presence or absence of plaque is insufficient to fully account for the deleterious role of elevated Abeta in AD. Such studies support the basis for an alternate interpretation of the Abeta cascade hypothesis. Namely, that soluble oligomers of Abeta (i.e., ADDLs) accumulate and cause functional deficits prior to overt neuronal cell death or plaque deposition. Accordingly, the following review focuses on research describing the preparation and functional activity of ADDLs in vitro and in vivo. These studies provide the basis for an alternate, ADDL-based, view of the Abeta cascade hypothesis and accounts for the disconnect between plaque burden and cognitive deficits. Possible therapeutic approaches aimed at lowering ADDLs in AD patients are also considered.

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Section: Addl Preparation and Isolationmentioning

confidence: 95%

Section: Addl Preparation and Isolationmentioning

confidence: 99%

The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimers Disease

Catalano

Dodson²,

Henze³

et al. 2006

CTMC

102

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“…The conformational and amyloid forming behaviour of penta(acetyl-Hmb)Ai 1 -40 was studied by circular dichroism and electron microscopy [95,97]. In the h-helix-inducing solvent trifluoroethanol, penta(acetyl-Hmb)Ai 1 -40 adopted approximately 25% h-helical structure and 70% random coil, compared with 81% h-helix for Ai 1 -40 .…”

Section: Synthetic Methods For the Preparation Of The A Sequencementioning

confidence: 99%

The amyloid‐β peptide and its role in Alzheimer's disease

Clippingdale

Wade

Barrow

2001

Journal of Peptide Science

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Amyloid formation plays a central role in the cause and progression of Alzheimer's disease. The major component of this amyloid is the amyloid-beta (A beta) peptide, which is currently the subject of intense study. This review discusses some recent studies in the area of A beta synthesis, purification and structural analysis. Also discussed are proposed mechanisms for A beta-induced neurotoxicity and some recent advances in the development of A beta-related therapeutic strategies.

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“…[1][2][3] These peptides often result in low yields and limited purities. 2,[4][5][6] Some examples are the amyloid forming peptides like amyloid-b (Ab), 2 a-synuclein, 7,8 and acyl carrier protein (ACP) 9,[65][66][67][68][69][70][71][72][73][74] and some hydrophobic transmembrane segments of proteins, like glycophorin A, epidermal growth factor (EGFR), and M2 ion channel. 10 The hydrophobic stretches in these peptides appear to promote aggregation during synthesis and purification (see below).…”

mentioning

confidence: 99%

“…These include photo-triggered interruption of amide bond formation with ester bonds (o-acyl isopeptide), [35][36][37] introduction of pseudoproline, which acts as a b-sheet breaker to prevent aggregation during coupling, 38 and the use of other chemical moieties to act as backbone protecting intermediates. 4,[39][40][41] Most of these techniques are useful in producing higher yields of hydrophobic peptides but are also, to varying degrees, cumbersome and expensive to undertake on a routine basis.…”

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confidence: 99%

Improved chemical synthesis of hydrophobic Aβ peptides using addition of C‐terminal lysines later removed by carboxypeptidase B

2014

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Many amyloidogenic peptides are highly hydrophobic, introducing significant challenges to obtaining high quality peptides by chemical synthesis. For example, while good yield and purity can be obtained in the solid phase synthesis of the Alzheimer’s plaque peptide Aβ40, addition of a C-terminal Ile-Ala sequence to generate the more toxic Aβ42 molecule creates a much more difficult synthesis resulting in low yields and purities. We describe here a new method that significantly improves the Fmoc solid phase synthesis of Aβ peptides. In our method, Lys residues are linked to the desired peptide’s C-terminus through standard peptide bonds during the synthesis. These Lys residues are then removed post-purification using immobilized carboxypeptidase B. With this method we obtained both Aβ42 and Aβ46 of superior quality that, for Aβ42, rivals that obtained by recombinant expression. Intriguingly, the method appears to provide independent beneficial effects on both the total synthetic yield and on purification yield and final purity. Reversible Lys addition with carboxypeptidase B removal should be a generally useful method for making hydrophobic peptides that is applicable to any sequence not ending in Arg or Lys. As expected from the additional hydrophobicity of Aβ46, which is extended from the sequence Aβ42 by a C-terminal Thr-Val-Ile-Val sequence, this peptide makes typical amyloid at rates significantly faster than for Aβ42 or Aβ40. The enhanced amyloidogenicity of Aβ46 suggests that, even though it is present in relatively low amounts in the human brain, it could play a significant role in helping to initiate Aβ amyloid formation.

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Secondary structural modifications of Aβ(1–40) induced by multiple 2-acetoxy-4-methoxybenzyl (acetylHmb) protection

Cited by 3 publications

References 17 publications

The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimers Disease

The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimers Disease

The amyloid‐β peptide and its role in Alzheimer's disease

Improved chemical synthesis of hydrophobic Aβ peptides using addition of C‐terminal lysines later removed by carboxypeptidase B

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