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Protein Science (2004), 13:703-713. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Lead optimization of antifungal peptides with 3D NMR structures analysis

Céline Landon1, Florent Barbault1,3, Michèle Legrain2, Laure Menin2,4, Marc Guenneugues2, Valérie Schott2, Françoise Vovelle1 and Jean-Luc Dimarcq2

1 Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique (CNRS), Unite Propre de Recherche (UPR) 4301, affiliated with Orléans University, Orléans, France
2 Entomed S.A., Illkirch, France

(RECEIVED September 3, 2003; FINAL REVISION November 7, 2003; ACCEPTED November 10, 2003)



Abstract

Antimicrobial peptides are key components of the innate immune response in most multicellular organisms. These molecules are considered as one of the most innovative class of anti-infective agents that have been discovered over the last two decades, and therefore, as a source of inspiration for novel drug design. Insect cystein-rich antimicrobial peptides with the CS{alpha}{beta} scaffold (an {alpha}-helix linked to a {beta}-sheet by two disulfide bridges) represent particularly attractive templates for the development of systemic agents owing to their remarkable resistance to protease degradation. We have selected heliomicin, a broad spectrum antifungal CS{alpha}{beta} peptide from Lepidoptera as the starting point of a lead optimization program based on phylogenic exploration and fine tuned mutagenesis. We report here the characterization, biological activity, and 3D structure of heliomicin improved analogs, namely the peptides ARD1, ETD-135, and ETD-151. The ARD1 peptide was initially purified from the immune hemolymph of the caterpillars of Archeoprepona demophoon. Although it differs from heliomicin by only two residues, it was found to be more active against the human pathogens Aspergillus fumigatus and Candida albicans. The peptides ETD-135 and ETD-151 were engineered by site-directed mutagenesis of ARD1 in either cationic or hydrophobic regions. ETD-135 and ETD-151 demonstrated an improved antifungal activity over the native peptides, heliomicin and ARD1. A comparative analysis of the 3D structure of the four molecules highlighted the direct impact of the modification of the amphipathic properties on the molecule potency. In addition, it allowed to characterize an optimal organization of cationic and hydrophobic regions to achieve best antifungal activity.

Keywords: insect immunity; antifungal; antimicrobial; heliomicin; NMR structure

Reprint requests to: Céline Landon, Centre de Biophysique Moléculaire, CNRS UPR4301, rue C. Sadron, 45071 Orléans cedex2, France; e-mail: landon{at}cnrs-orleans.fr; fax: 33-2-38-63-15-17.

Supplemental material: see www.proteinscience.org

3 Present addresses: Institut de Topologie et de Dynamique des Systémes, CNRS UPESA 7086, 1 rue Guy de la Brosse, 75005 Paris, France;

4 Geneprot, 2 rue du Pré-de-la-Fontaine, 1217 Meyrin, Switzerland.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03404404.


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