Synthesis and Characterization of Hairpin Mimics that Modulate the Early Oligomerization and Fibrillization of Amyloid β‐Peptide. Issue 20 (31st May 2017)

• Record Type: Journal Article
• Authors: Vahdati, Leila; Kaffy, Julia; Brinet, Dimitri; Bernadat, Guillaume; Correia, Isabelle; Panzeri, Silvia; Fanelli, Roberto; Lequin, Olivier; Taverna, Myriam; Ongeri, Sandrine; Piarulli, Umberto
• Is Part Of: European journal of organic chemistry. Issue 20(2017)
• Page Start: 2971
• Page End: 2980
• Publication Date: 2017-05-31
• Subjects: Amyloid β‐peptides -- Protein‐protein interactions -- Alzheimer's disease -- Protein folding -- Hairpins -- Peptidomimetics; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201700010
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract : 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. Abstract : A small hairpin mimic, containing a cis ‐diketopiperazine scaffold as a turn inducer, is able to decrease the aggregation of amyloid peptide Aβ1–42 and prevent the formation of oligomeric and neurotoxic species.