Journal article
Structure–Activity Studies of β-Hairpin Peptide Inhibitors of the Plasmodium falciparum AMA1–RON2 Interaction
G Wang, N Drinkwater, DR Drew, CA MacRaild, DK Chalmers, B Mohanty, SS Lim, RF Anders, JG Beeson, PE Thompson, S McGowan, JS Simpson, RS Norton, MJ Scanlon
Journal of Molecular Biology | ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD | Published : 2016
Abstract
The interaction between apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) plays a key role in the invasion of red blood cells by Plasmodium parasites. Disruption of this critical protein–protein interaction represents a promising avenue for antimalarial drug discovery. In this work, we exploited a 13-residue β-hairpin based on the C-terminal loop of RON2 to probe a conserved binding site on Plasmodium falciparum AMA1. A series of mutations was synthetically engineered into β-hairpin peptides to establish structure–activity relationships. The best mutations improved the binding affinity of the β-hairpin peptide by ~ 7-fold for 3D7 AMA1 and ~ 14-fold for FVO AMA1. We determine..
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Grants
Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank Boew Keat Yap and Kade Roberts for technical assistance in peptide synthesis. G.W. acknowledges support from the Monash University Postgraduate Publication Award Scheme. R.S.N. and J.G.B. acknowledge fellowship support from the National Health and Medical Research Council of Australia. This work was supported in part by the National Health and Medical Research Council (project grant 1025150 and program grant 637406). We thank the Australian Synchrotron for beam time (MXCAP 8208) and technical assistance. The Burnet Institute is supported by the NHMRC Independent Research Institutes Infrastructure Support Scheme and the Operational Infrastructure Support from the Victorian State Government.