Design of β-amyloid aggregation inhibitors from a predicted structural motif.

Drug design studies targeting one of the primary toxic agents in Alzheimer's disease, soluble oligomers of amyloid β-protein (Aβ), have been complicated by the rapid, heterogeneous aggregation of Aβ and the resulting difficulty to structurally characterize the peptide. To address this, we have developed [Nle(35), D-Pro(37)]Aβ(42), a substituted peptide inspired from molecular dynamics simulations which forms structures stable enough to be analyzed by NMR. We report herein that [Nle(35), D-Pro(37)]Aβ(42) stabilizes the trimer and prevents mature fibril and β-sheet formation.

A molecular dynamics study of the interaction of D-peptide amyloid inhibitors with their target sequence reveals a potential inhibitory pharmacophore conformation.

The self-assembly of soluble proteins and peptides into beta-sheet-rich oligomeric structures and insoluble fibrils is a hallmark of a large number of human diseases known as amyloid diseases. Drugs that are able to interfere with these processes may be able to prevent and/or cure these diseases. Experimental difficulties in the characterization of the intermediates involved in the amyloid formation process have seriously hampered the application of rational drug design approaches to the inhibition of amyloid formation and growth.

New strategy for the generation of specific D-peptide amyloid inhibitors.

The conversion of a soluble protein into beta-sheet-rich oligomeric structures and further fiber formation are critical steps in the pathogenesis of the group of human diseases known as amyloidoses. Drugs that interfere with this process may thus be able to prevent and/or cure these diseases. Recent results have shown that short amino acid stretches can provide most of the driving force needed to trigger amyloid formation of a protein.

Amyloid toxicity is independent of polypeptide sequence, length and chirality.

By using an amyloid sequence pattern, here we have identified putative six-residue amyloidogenic stretches in several relevant amyloid proteins. Hexapeptides synthesized on the bases of the sequence stretches matching the pattern have been shown to form amyloid fibrils in vitro. As larger pathological peptides such as A beta(1-42) do, these short amyloid peptides form heterogeneous mixtures of small aggregates that induce cell death in PC12 cells and primary hippocampal neurons.

Hacking the code of amyloid formation: the amyloid stretch hypothesis.

Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation.

Peptide model systems for amyloid fiber formation: design strategies and validation methods.

The rational understanding of the factors involved in the formation of amyloid deposits in tissue is fundamental to the identification of novel therapeutic strategies to prevent or cure pathological conditions such as Alzheimer's and Parkinson's disease or spongiform encephalopathies. Given the complexity of the molecular events driving protein self-association, a frequent strategy in the field has consisted of designing simplified model systems that facilitate the analysis of the elements that predispose polypeptides toward amyloid formation. In fact, these systems have provided very valuable knowledge on the determinants underlying structural transitions to the polymeric beta-sheet state present in amyloid fibers and more disordered aggregates.

The amyloid stretch hypothesis: recruiting proteins toward the dark side.

A detailed understanding of the molecular events underlying the conversion and self-association of normally soluble proteins into amyloid fibrils is fundamental to the identification of therapeutic strategies to prevent or cure amyloid-related disorders. Recent investigations indicate that amyloid fibril formation is not just a general property of the polypeptide backbone depending on external factors, but that it is strongly modulated by amino acid side chains. Here, we propose and address the validation of the premise that the amyloidogenicity of a protein is indeed localized in short protein stretches (amyloid stretch hypothesis).

Design of model systems for amyloid formation: lessons for prediction and inhibition.

The determination of the physico-chemical principles underlying amyloid deposition is fundamental to the identification of therapeutic strategies to prevent or cure amyloid-related disorders. Given the complexity of the molecular events involved in protein self-association, researchers have designed simplified systems that facilitate the discovery of factors that predispose polypeptides to amyloid formation and aggregation. These systems have provided valuable knowledge about the determinants underlying the structural transitions to the polymeric beta-sheet state present in amyloid fibers and in more disordered aggregates.