Capped Gly-Gly-Ala inhibits β−sheet formation and aggregation in peptides associated with neurodegenerative disease

•β−sheets and their unfolding are monitored by infrared spectroscopy.•We present a tripeptide capable of reversing β−sheet formation in other peptides.•Our inhibitor can completely eliminate β−sheets from α−Synuclein-derived peptides.•Our inhibitor can dramatically reduce β−sheet formation in Aβ(16−22). A wide array of protein misfolding diseases all follow a similar pathogenic mechanism that includes, as an early step, the formation of β−sheet-rich monomers and oligomers. Thus, interruption of β−sheets is a promising strategy for preventing and reversing these diseases. We have identified a tri-peptide that is capable of interacting with peptides that can form β−sheets in isolation, and causing their unfolding. Using infrared spectroscopy, we studied the effect of Ac-GGA-NH2, a disordered peptide, on four β−sheet peptides derived from stretches of amyloidogenic proteins. In each case, less β−sheet is observed in the experimental mixture of these peptides and Ac-GGA-NH2 than is predicted mathematically from averaging the individual spectra of the two peptides. In the case of the two peptides we used that are derived from α−Synuclein, complete unfolding of the β−sheets is induced by the presence of equimolar concentrations of Ac-GGA-NH2.