Disruption of the AMA1–RON2 interaction in the invasion of red blood cells by malarial parasites represents a promising avenue for antimalarial drug discovery.

A 13-residue β-hairpin based on the C-terminal loop of RON2 was used to probe a conserved binding site on AMA1 and facilitated the identification of two beneficial interactions.

Crystal structures of several β-hairpin peptides in complex with AMA1 have been determined to define the structural features that contribute to improved binding affinity.

Introduction of two beneficial mutations into the longer RON2sp2 peptide produced the most potent strain-transcending peptide inhibitor reported for AMA1 to date.