Drugs designed to treat diseases like Alzheimer's, type II diabetes and Parkinson's could soon be improved thanks to chemists from Sweden and Thailand who have obtained high resolution X-ray structures of poly-N-methylated alpha-peptides.

N-methylated peptides can inhibit amyloidosis, the build-up of proteins thought to be responsible for such diseases. N-methylation is thought to change the peptide conformation and it has been generally assumed that N-methylated amino acids and peptides adopt a beta-strand structure. However until now, no high resolution structural analysis has been available to confirm this assumption.

Per Arvidsson and colleagues from Uppsala University and Mahidol University made poly-N-methylated peptides and used high resolution X-ray diffraction analysis to confirm that N-methylated peptides do indeed adopt a beta-strand conformation.

Arvidsson also showed that N-methylated peptides form hydrogen bonds with alpha-peptides. The N-methyl substituent prevents beta-sheet formation of the alpha-peptides thus preventing aggregation and consequently amyloidosis. These findings also explain why alpha-peptides with alternating N-methyl amino acids are more potent inhibitors of amyloidosis. The X-ray structures will 'help in the design of more potent anti-amyloidosis agents, as well as other sheet-containing molecular constructs,' said Arvidsson.

Rebecca I Gillan