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

Alzheimer’s disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides, with Aβ1-42 being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of Aβ1-42-amyloid related β-hairpin peptidomimetics, built on a piperidine-pyrrolidine semi rigid β-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of Aβ1-42. According to these peptide sequences, a stable β-hairpin or a dynamic equilibrium between two possible architectures was observed. These original constructs are able to greatly delay the kinetics of Aβ1-42 aggregation process as demonstrated by thioflavin-T fluorescence, and transmission electron microscopy. Capillary electrophoresis indicates their ability to preserve the monomer species, inhibiting the formation of toxic oligomers. Furthermore, compounds protect against toxic effects of Aβ on neuroblastoma cells even at substoichiometric concentrations. This study is the first example of acyclic small β-hairpin mimics possessing such a highly efficient anti-aggregation activity. The protective effect is more pronounced than that observed with molecules which have undergone clinical trials. The structural elements made in this study provide valuable insights in the understanding of the aggregation process and insights to explore the design of novel acyclic β-hairpin targeting other types of amyloid-forming proteins

Tissue heterogeneity, composite architecture and fractal dimension effects in the fracture of ageing human bone

The mechanical characteristics of human bone, especially those relating to age, are of immense interest to everyone. A great amount of information has already been accumulated on the macromechanical/phenomenological aspects of bone behaviour and while some aspects, such as stiffness and strength, have been attributed to effects at the architectural/compositional level, some others like toughness have been related to events at the molecular/biophysical level. It is not always easy to unravel the intimate relationship between the architectural and remodelling changes at the macroscale to the biophysical/chemical effects occurring at the ultrastructural level. There is however, the mesostructural level (fractography), which is commonly overlooked or has been approached in a purely qualitative manner. In this article we concentrated primarily on the variation of toughness of ageing bone with age and then examined the fracture profile morphology of the various samples by fractal analysis. The results show that the way bone actually fractures, in either slow/ductile or fast/brittle fracture, has an underlying connection to the architectural status of each individual and the way ageing bone changes as a 'material' as well as a 'collection' of heterogeneous elements and structures. Of course, fracture morphology cannot simply and uniquely be described by one fractal dimension, but fracture nevertheless is determined by the intrinsic architecture of the bone structure and its material. © Springer 2006

Proteolytically Stable Diaza-Peptide Foldamers Mimic Helical Hot Spots of Protein-Protein Interactions and Act as Natural Chaperones

: A novel class of peptidomimetic foldamers based on diaza-peptide units are reported. Circular dichroism, attenuated total reflection -Fourier transform infrared, NMR, and molecular dynamics studies demonstrate that unlike the natural parent nonapeptide, the specific incorporation of one diaza-peptide unit at the N-terminus allows helical folding in water, which is further reinforced by the introduction of a second unit at the C-terminus. The ability of these foldamers to resist proteolysis, to mimic the small helical hot spot of transthyretin-amyloid β (Aβ) cross-interaction, and to decrease pathological Aβ aggregation demonstrates that the introduction of diaza-peptide units is a valid approach for designing mimics or inhibitors of protein-protein interaction and other therapeutic peptidomimetics. This study also reveals that small peptide foldamers can play the same role as physiological chaperone proteins and opens a new way to design inhibitors of amyloid protein aggregation, a hallmark of more than 20 serious human diseases such as Alzheimer's disease

Structure-activity relationships of β-hairpin mimics as modulators of amyloid β-peptide aggregation

Aggregation of amyloid proteins is currently involved in more than 20 serious human diseases that are actually untreated, such as Alzheimer's disease (AD). Despite many efforts made to target the amyloid cascade in AD, finding an aggregation inhibiting compound and especially modulating early oligomerization remains a relevant and challenging strategy.We report herein the first examples of small and nonpeptide mimics of acyclic beta-hairpins, showing an ability to delay the fibrillization of amyloid-b (Ab1- 42) peptide and deeply modify its early oligomerization process. Modifications providing better druggability properties such as increased hydrophilicity and reduced peptidic character were performed. We also demonstrate that an appropriate balance between flexibility and stability of the b-hairpin must be reached to adapt to the different shape of the various aggregated forms of the amyloid peptide. This strategy can be investigated to target other challenging amyloid proteins