A glutamine-based single α-helix scaffold to target globular proteins

The binding of intrinsically disordered proteins to globular ones can require the folding of motifs into alpha-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single alpha-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single alpha-helices for a wide range of applications in protein engineering and drug design. Targeting biomedically relevant protein-protein interactions is a long-lasting challenge in medicinal chemistry. Here, the authors develop a single alpha-helical peptide scaffold that can be tailored to target globular proteins of biomedical interest.

Automated summary

This study presents design rules for creating peptides that fold into single alpha-helices by utilizing glutamine side chain to main chain hydrogen bonds. These peptides can be used to target globular proteins and have a wide range of applications.