Introducing sequential aza-amino acids units induces repeated β-turns and helical conformations in peptides

Tonali, Nicolò; Correia, Isabelle; Lesma, Jacopo; Bernadat, Guillaume; Ongeri, Sandrine; Lequin, Olivier

doi:10.1039/c9ob02654a

Cited by 10 publications

(22 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2), serving as a reference with respect to our previously published work. 23 Different NMR parameters were analysed to assess the hydrogen bonding and folding propensities of diaza-tripeptides, in particular the temperature dependency of the amide proton chemical shift (temperature coefficient Δ δ HN /Δ T ) and the through-space dipolar 1 H– 1 H ROE correlations.…”

Section: Resultsmentioning

confidence: 99%

Two consecutive aza-amino acids in peptides promote stable β-turn formation in water

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Two consecutive aza-amino acids in peptides promote stable β-turn formation in water

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Finally, one α/aza/aza/pseudotripeptide, Phe-azaLys-azaVal-COCH 3 (abbreviated as FaLaV-COCH 3 ) mimicking the C -terminal arm FLV of 8 , was inserted in compounds 13 and 14 and evaluated alone (compound 15 ). The introduction of one aza-amino acid in peptides has shown significant success in providing biologically active peptides (see the references cited in Tonali et al, 2020 ). However, to our knowledge, only scarce examples of biologically active peptide mimics having two consecutive aza-amino acids have been reported ( Gante et al, 1995 ; Han et al, 1998 ).…”

Section: Resultsmentioning

confidence: 99%

β-Hairpin Peptide Mimics Decrease Human Islet Amyloid Polypeptide (hIAPP) Aggregation

Lesma¹,

Bizet²,

Berardet³

et al. 2021

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1–42) as a successful strategy to inhibit its aggregation involved in Alzheimer’s disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.

show abstract

“…These findings highlight the fact that the design of TTR-derived anti-Aβ agents requires a correct balance between advantages and disadvantages of using a protein versus peptide as therapeutic, and a compromise between efficacy, specificity, stability and conformational behavior is demanding. This consideration opens the way to the use of peptidomimetic foldamers, for example, as a new approach which might resolve a major issue in the use of peptides as drugs, by stabilizing secondary conformations similar to natural peptides and retaining the selectivity due to the lateral chains [156].…”

Section: Ttr-aβ Interaction-based Strategies To Design Anti-aβ Agentsmentioning

confidence: 99%

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

et al. 2020

Self Cite

View full text Add to dashboard Cite

Alzheimer’s disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions.

show abstract

Introducing sequential aza-amino acids units induces repeated β-turns and helical conformations in peptides

Abstract: A major current issue in medicinal chemistry is the design of small peptide analogues resistant to proteolysis and able to adopt preferential conformations, while preserving the selectivity and efficiency of natural peptides.

Cited by 10 publications

References 45 publications

Two consecutive aza-amino acids in peptides promote stable β-turn formation in water

Two consecutive aza-amino acids in peptides promote stable β-turn formation in water

β-Hairpin Peptide Mimics Decrease Human Islet Amyloid Polypeptide (hIAPP) Aggregation

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

Contact Info

Product

Resources

About