Anti-amyloidogenic Heterocyclic Peptides

Abstract

The amyloid fibril is a highly ordered proteinous aggregate, originally discovered in the context of the self-assembly of soluble proteins into insoluble extracellular plaques. The molecular structure of amyloidosis, an energetically stable conformation with a thermodynamic local minimum, is of particular interest because of its possible pathogenicity. Amyloidogenic diseases (amyloidoses) are often fatal, widely heterogenic, and caused by sporadic, genetic, or infectious pathogens. Consequently, major effort has been directed in the past few decades to identify and develop agents that decrease the concentration of the pathogenic aggregates either by interfering with the self-assembly of the proteins or by modulating their physiological concentration. Heterocyclic peptides of natural and synthetic origin have gained special attention because of their demonstrated ability to interact with various amyloids. In addition to interfering with the amyloid aggregation process, many of the discovered peptides also inhibit the formation of fibrils, disassemble preformed fibrils, and prevent the pathogenic seeding effect. Others are instrumental candidates for passive vaccination against amyloid deposits. The promising preliminary results described here, together with the broad chemical diversity of heterocyclic peptides and their amenability to largescale production, make these compounds promising for anti-amyloidogenic research and for pharmacological therapy of amyloidoses.

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

“… 6 A variety of small peptides that inhibit aggregation of Aβ and reduce its toxic effects have been already described. 7 In particular, inhibition of Aβ-aggregation has been targeted using self-recognition elements (SREs). Indeed, molecules based on fragments of the Aβ-peptide, essentially on the nucleation sequence Aβ 16–20 (KLVFF), were found promising as SREs.…”