The influence of backbone fluorination on the helicity of α/γ-hybrid peptides

Peptides that are composed of an alternating pattern of alpha- and gamma-amino acids are potentially valuable as metabolism-resistant bioactive agents. For optimal function, some kind of conformational restriction is usually required to either stabilize the dominant 12-helix, or else to divert the peptide away from this conformation in a controlled way. Herein, we explore stereoselective fluorination as a method for controlling the conformations of alpha/gamma-hybrid peptides. We show through a combination of X-ray, NMR and CD analyses that fluorination can either stabilize or disrupt the 12-helix, depending on the fluorine stereochemistry. These findings could inform the ongoing development of diverse functional hybrid peptides. Incorporating fluorine atoms into the backbone of an alpha/gamma-hybrid peptide is shown to either stabilize or break the 12-helix, depending on the fluorine stereochemistry. Fluorine can also set the handedness of the helix.