Switch-peptides

Design and characterization of controllable super-amyloid-forming host-guest peptides as tools for identifying anti-amyloid agents

Marie Stéphanie Camus, Sonia Dos Santos, Arunan Chandravarkar, Bhubaneswar Mandal, Adrian W. Schmid, Gabriele Tuchscherer, Manfred Mutter, Hilal A. Lashuel

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Several amyloid-forming protiens are characterized by the presence of hydrophobic and highly amyloidogenic core sequences that play critical roles in the initiation and progression of amyloid fibril formation. Therefore targeting these sequences represents a viable strategy for identifying candidate molecules that could interfere with amyloid formation and toxicity of the parent protiens. However, the highly amyloidogenic and insoluble nature of these sequences has hampered efforts to develop high-throughput fibrillization assays. Here we describe the design and characterization of host-guest switch peptides that can be used for in vitro mechanistic and screening studies that are aimed at discovering aggregation inhibitors that target highly amyloidogenic sequences. These model systems are based on a host-guest system where the amyloidogenic sequence (guest peptide) is flanked by two β-sheet-promoting (Leu-Ser)n oligomers as host sequences. Two host-guest peptides were prepared by using the hydrophobic core of Aβ comprising residues 14-24 (HQKLVFF-AEDV) as the guest peptide with switch elements inserted within (peptide 1) or at the N and C termini of the guest peptide (peptide 2). Both model peptides can be triggered to undergo rapid self-assembly and amyloid formation is a higly controllable manner and their fibrillization kinetics is tuneable by manipulating solution conditions (for example, peptide concentration and pH). The fibrillization of both peptides and can be inhibited by known inhibitors of Aβ fibril formation. Our results suggest that this approach can be extended to other amyloid proteins and should facilitate the discovery of small-molecule aggregation inhibitors and the development of more efficacious anti-amyloid agents to treat and/or reverse the pathogenesis of neurodegenerative and systemic amyloid diseases.

Original languageEnglish
Pages (from-to)2104-2112
Number of pages9
JournalChemBioChem
Volume9
Issue number13
DOIs
Publication statusPublished - 1 Sep 2008
Externally publishedYes

Fingerprint

Amyloid
Switches
Peptides
Agglomeration
Amyloidogenic Proteins
Molecules
Oligomers
Self assembly
Toxicity
Assays
Screening
Throughput
Kinetics

Keywords

  • Aggregation
  • Alzheimer's disease
  • Amyloid fibrils
  • Conformation analysis
  • Host-guest switch peptides

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology

Cite this

Camus, M. S., Dos Santos, S., Chandravarkar, A., Mandal, B., Schmid, A. W., Tuchscherer, G., ... Lashuel, H. A. (2008). Switch-peptides: Design and characterization of controllable super-amyloid-forming host-guest peptides as tools for identifying anti-amyloid agents. ChemBioChem, 9(13), 2104-2112. https://doi.org/10.1002/cbic.200800245

Switch-peptides : Design and characterization of controllable super-amyloid-forming host-guest peptides as tools for identifying anti-amyloid agents. / Camus, Marie Stéphanie; Dos Santos, Sonia; Chandravarkar, Arunan; Mandal, Bhubaneswar; Schmid, Adrian W.; Tuchscherer, Gabriele; Mutter, Manfred; Lashuel, Hilal A.

In: ChemBioChem, Vol. 9, No. 13, 01.09.2008, p. 2104-2112.

Research output: Contribution to journalArticle

Camus, MS, Dos Santos, S, Chandravarkar, A, Mandal, B, Schmid, AW, Tuchscherer, G, Mutter, M & Lashuel, HA 2008, 'Switch-peptides: Design and characterization of controllable super-amyloid-forming host-guest peptides as tools for identifying anti-amyloid agents', ChemBioChem, vol. 9, no. 13, pp. 2104-2112. https://doi.org/10.1002/cbic.200800245
Camus, Marie Stéphanie ; Dos Santos, Sonia ; Chandravarkar, Arunan ; Mandal, Bhubaneswar ; Schmid, Adrian W. ; Tuchscherer, Gabriele ; Mutter, Manfred ; Lashuel, Hilal A. / Switch-peptides : Design and characterization of controllable super-amyloid-forming host-guest peptides as tools for identifying anti-amyloid agents. In: ChemBioChem. 2008 ; Vol. 9, No. 13. pp. 2104-2112.
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