Home » Key Scientific Articles » In vitro and mechanistic studies of an antiamyloidogenic self-assembled cyclic D,L-{Alpha}-peptide architecture.

In vitro and mechanistic studies of an antiamyloidogenic self-assembled cyclic D,L-{Alpha}-peptide architecture.

Richman M, Wilk S, Chemerovski M, Wärmländer SK, Wahlström A, Gräslund A, Rahimipour S.

J Am Chem Soc. 2013 Mar 6;135(9):3474-84.

Department of Chemistry, Bar-Ilan University, Ramat-Gan 5290, Israel.

 

Abstract

 

Misfolding of the A{Beta} protein and its subsequent aggregation into toxic oligomers are related to Alzheimer’s disease. Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction. Given the significant similarities between amyloids and the architecture of self-assembled cyclic D,L-{Alpha}-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of A{Beta}, thereby preventing its aggregation into toxic forms. By screening a focused library of six-residuecyclic D,L-{Alpha}-peptides and optimizing the activity of a lead peptide, we found one cyclic D,L-{Alpha}-peptide (CP-2) that interacts strongly with A{Beta} and inhibits its aggregation. In transmission electron microscopy, optimized thioflavin T and cell survival assays, CP-2 inhibits the formation of A{Beta} aggregates, entirely disassembles preformed aggregated and fibrillar A{Beta}, and protects rat pheochromocytoma PC12 cells from A{Beta} toxicity, without inducing any toxicity by itself. Using various immunoassays, circular dichroism spectroscopy, photoinduced cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE, and NMR, we probed the mechanisms underlying CP-2’s antiamyloidogenic activity. NMR spectroscopy indicates that CP-2 interacts with A{Beta} through its self-assembled conformation and induces weak secondary structure in A{Beta}. Upon coincubation, CP-2 changes the aggregation pathway of A{Beta} and alters its oligomer distribution by stabilizing small oligomers (1-3 mers). Our results support studiessuggesting that toxic early oligomeric states of A{Beta} may be composed of antiparallel {Beta}-peptide structures and that the interaction of A{Beta} with CP-2 promotes formation of more benign parallel {Beta}-structures. Further studies will show whether these kinds of abiotic cyclic D,L-{Alpha}-peptides are also beneficial as an intervention in related in vivo models.

 

 

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