β-Hairpin mimics containing a piperidine–pyrrolidine scaffold modulate the β-amyloid aggregation process preserving the monomer species

Pellegrino, Sara; Tonali, Nicolò; Erba, Emanuela; Kaffy, Julia; Taverna, Myriam; Contini, Alessandro; Taylor, Mark; Gelmi, Maria Luisa; Ongeri, Sandrine

doi:10.1039/c6sc03176e

Cited by 40 publications

(74 citation statements)

References 74 publications

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“…Some of the synthetic approaches used to generate peptidomimetics as aggregation modulators include backbone modication, side chain modication, the introduction of specic organic moieties and cyclization. 81,[85][86][87] As has already been suggested, the inhibition of aggregation alone is not sufficient to tackle the multifactorial pathology of AD. Therefore, multifunctional peptidomimetic-based aggregation modulators have been developed, which are capable of targeting other pathophysiological factors involved in AD.…”

Section: Targeting Ab and Tau Aggregationmentioning

confidence: 99%

Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease

2018

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Section: Targeting Ab and Tau Aggregationmentioning

confidence: 99%

Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease

2018

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“…Recently, the assumption that preorganized strands in β‐hairpin mimics will promote the association and sheet formation with Aβ 1–42 thus preventing, or at least delaying its aggregation, has been validated by macrocyclic β‐sheet mimic structures , . However, to our knowledge, only rare examples of acyclic β‐hairpins have been demonstrated as Aβ 1–42 binders and inhibitors of aggregation . On the other hand, the exclusive or very high peptidic character of these compounds would clearly hamper their development as drugs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Hairpin Mimics that Modulate the Early Oligomerization and Fibrillization of Amyloid β‐Peptide

et al. 2017

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Alzheimer's disease is a neurodegenerative disorder that is linked to oligomerization and fibrillization of different amyloid β‐peptide isoforms. Among these amyloid peptides, Aβ1–42 is considered the most aggregative and neurotoxic species. We report herein the synthesis of four β‐sheet mimics composed of a peptidomimetic arm based on a 5‐amino‐2‐methoxy benzhydrazide derivative, a 2,5‐diketopiperazine scaffold (either cis‐DKP or trans‐DKP) and a tetrapeptide sequence (either Gly‐Val‐Val‐Ile, GVVI, or Lys‐Leu‐Val‐Phe, KLVF). The derivatives containing the cis‐DKP were shown by NMR and computational studies to adopt a stable β‐hairpin conformation in solution, whereas the trans‐DKP scaffold promoted the formation of extended structures. The activity of these compounds in modulating the aggregation of Aβ1–42 peptide was investigated by conducting Thioflavin T fluorescence assays to measure the kinetics of aggregation. Capillary electrophoresis (CE) and transmission electron microscopy (TEM) were then used to monitor the formation of small soluble Aβ oligomers and higher molecular weight and insoluble Aβ aggregates, respectively. As a result, small hairpin mimics containing the cis‐DKP scaffold were found to prevent the formation of small Aβ1–42 oligomeric and neurotoxic species.

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“…REMD simulations of peptides 10 and m10 were performed according to a protocol described previously . Briefly, simulations were conducted by using the ff96 force field, coupled with the generalised Born model OBC(II).…”

Section: Methodsmentioning

confidence: 99%

“…The synthesis of non‐natural amino acids and scaffolds to be used as turn mimics,,, as well as their use to prepare peptide model sequences–, and PPI inhibitors, is one of our main research fields.…”

Section: Introductionmentioning

confidence: 99%

Tandem Tetrahydroisoquinoline‐4‐carboxylic Acid/β‐Alanine as a New Construct Able To Induce a Flexible Turn

Bucci

Bonetti

Clerici

et al. 2017

Chemistry A European J

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Tetrahydroisoquinoline-4-carboxylic acid, a constrained β -amino acid named β-TIC, was synthesised for the first time in enantiopure form. The biocatalytic route applied herein represents one of the few successful examples of enzymatic resolution of β -amino acids. Model tetrapeptides, namely, Fmoc-l-Ala-β-TIC-β-Ala-l-Val-OBn (Fmoc=fluorenylmethyloxycarbonyl, Bn=benzyl), containing both isomers of β-TIC, were prepared. Both computational and NMR spectroscopy studies were performed. A reverse-turn conformation was observed in the case of (R)-β-TIC enantiomer that was obtained in 99 % enantiomeric excess by enzymatic resolution. The β-TIC/β-Ala construct represents the first example of a flexible turn mimetic containing a cyclic and an acyclic β-amino acid. Furthermore, the presence of an aromatic ring of β-TIC could facilitate non-covalent interactions to increase the potential of this scaffold for the preparation of protein-protein interaction modulators.

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β-Hairpin mimics containing a piperidine–pyrrolidine scaffold modulate the β-amyloid aggregation process preserving the monomer species

Abstract: Acyclic β-hairpins designed on oligomeric and fibril structures of Aβ1–42 disrupt protein–protein interactions mediating amyloid β-peptide aggregation.

Cited by 40 publications

References 74 publications

Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease

Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease

Synthesis and Characterization of Hairpin Mimics that Modulate the Early Oligomerization and Fibrillization of Amyloid β‐Peptide

Tandem Tetrahydroisoquinoline‐4‐carboxylic Acid/β‐Alanine as a New Construct Able To Induce a Flexible Turn

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