Rational Design of Peptide Inhibitor Against Amyloidogenesis-Correlated Membrane Disruption by Merozoite Surface Protein 2

Abstract

New drugs and vaccines are urgently needed for malaria control owing to the increasing prevalence of drug-resistant Plasmodium strains. Malarial merozoite surface protein 2 (MSP2), potentially playing a role in parasite invasion into the host red blood cells, could be a target for anti-malaria drug development. MSP2 is suggested to cause membrane disruption that is correlated with amyloidogenesis of the protein, and thus peptides that can inhibit this property may be exploited as drug candidates against malaria. In this study, we designed peptides by introducing residues that favor β-turn formation into the amyloidogenic N-terminal segment between the 8th and 22nd residues of MSP2 (MSP28–22), and evaluated the ability of these derivative peptides to inhibit MSP2 amyloidogenesis and membrane disruption. One of the derivative peptides, M5, with a β-turn-prone sequence DPDG being inserted within MSP28–22, though did not form a rigid β-turn structure, did inhibit aggregation and membrane interaction by both itself and the wild-type peptide. Insertion of a β-turn-prone sequence may thus be a potential strategy to develop safe and effective peptide inhibitors against amyloidogeneic protein/peptide.