Comprehensive N-methyl scanning of a potent peptide inhibitor of malaria invasion into erythrocytes leads to pharmacokinetic optimization of the molecule
Date
2008
Authors
Scanlon, D.
Harris, K.
Coley, A.
Karas, J.
Casey, J.
Hughes, A.
Foley, M.
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Journal article
Citation
International Journal of Peptide Research and Therapeutics, 2008; 14(4):381-386
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Denis Scanlon, Karen S. Harris, Andrew M. Coley, John A. Karas, Joanne L. Casey, Andrew B. Hughes, Michael Foley
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Abstract
Apical membrane antigen-1 is a protein found in the merozoite stage of the malaria parasite Plasmodium falciparum and has been shown to be critical in the invasion of host erythrocytes. Using a random peptide library displayed on the surface of phage, a 20-residue peptide, R1 (VFAEFLPLFSKFGSRMHILK), was identified which specifically recognized and bound to P. falciparum AMA-1. Moreover, the peptide was found to competitively inhibit parasite invasion of red blood cells (RBC). In this study we report the synthesis and properties of the R1 peptide modified by comprehensive N-methyl scanning along the backbone of the peptide. The native R1 and eighteen R1 analogues containing single N-methyl substitutions were synthesized by manual solid-phase Fmoc peptide chemistry. The set of N-methylated peptides was assessed for relative binding affinity with Pf AMA-1 and RBC invasion inhibitory ability. N-methylation in positions 1, 8, and 14 in the R1 peptide produced analogues exhibiting stronger binding characteristics to Pf AMA-1. A tri N-methylated peptide was more than 10 times more active in the inhibition of RBC invasion assay. This peptide also exhibited enhanced serum stability which may be partially responsible for the increase in binding and bioactivity. We have therefore shown that modifications to a biologically active peptide can dramatically enhance activity and potentially provide a lead to a peptide therapeutic molecule with optimized pharmacokinetic properties.
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© Springer Science+Business Media, LLC 2008