A three stranded β-sheet peptide in aqueous solution containing N-methyl amino acids to prevent aggregation

Inhibition of Toxicity in the β-Amyloid Peptide Fragment β-(25–35) Using N-Methylated Derivatives

“…␤-(25-35) is very toxic and, according to previous work, requires only nanomolar levels to have an effect (2), although we find toxicity is apparent only above 1 M. It is therefore not surprising that although some inhibition is seen when NMeGly 33 is added to aggregated ␤- (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), showing that the peptide must be in a dynamic state of equilibrium between the folded and unfolded state, inhibition works best when added to unfolded ␤-(25-35) before applying conditions that promote aggregation. Previous work done with ␤-sheet breaker peptides on full-length A␤ has proved effective to varying degrees (20, 22-27, 37, 38), and this provides encouragement that if NMe derivatives of ␤-(25-35) are added to ␤-(1-42) they will be able to disrupt the aggregation and toxicity of this peptide also.…”

“…As it is highly toxic and forms fibrillar aggregates typical of ␤-amyloid, it is suitable as a model for testing inhibitors of aggregation and toxicity. We demonstrate that N-methylated derivatives of ␤- (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), which in isolation are soluble and non-toxic, can prevent the aggregation and inhibit the resulting toxicity of the wild type peptide. N-Methylation can block hydrogen bonding on the outer edge of the assembling amyloid.…”

“…We demonstrate that these can both prevent the aggregation of fibrils and inhibit the resulting toxicity. These peptides may have the potential to fold correctly and remain soluble in either monomeric or dimeric form.N-Methylation is known to promote ␤-sheet formation by locking the residue into a ␤ conformation (28), it and has been shown to generate soluble monomeric ␤-sheet peptides (29). By N-methylating the amide NH groups at the outer edges of the ␤-sheet and so prevent intermolecular hydrogen bonding, both aggregation and toxicity should be prevented.…”

“…Of all of the A␤ derivatives studied so far, ␤- (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), sequence GSNKGAIIGLM, is the shortest fragment that exhibits large ␤-sheet fibrils and retains the toxicity of the full-length peptide (2,(7)(8)(9). It has been proposed that ␤- (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) represents the biologically active region of A␤.…”

“…␤- (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)) is a synthetic derivative of ␤-amyloid, the peptide that is believed to cause Alzheimer's disease. As it is highly toxic and forms fibrillar aggregates typical of ␤-amyloid, it is suitable as a model for testing inhibitors of aggregation and toxicity.…”