Lead optimization of antifungal peptides with 3D NMR structures analysis

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 nove...

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Bibliographic Details
Published in:Protein science 2004-03, Vol.13 (3), p.703-713
Main Authors: Landon, Céline, Barbault, Florent, Legrain, Michèle, Menin, Laure, Guenneugues, Marc, Schott, Valérie, Vovelle, Françoise, Dimarcq, Jean‐Luc
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
antifungal
Antifungal Agents - chemistry
Antifungal Agents - pharmacology
antimicrobial
Antimicrobial Cationic Peptides - chemistry
Antimicrobial Cationic Peptides - genetics
Antimicrobial Cationic Peptides - pharmacology
Aspergillus fumigatus - drug effects
Candida albicans - drug effects
Cloning, Molecular
Cryptococcus neoformans - drug effects
Drug Design
Fusarium - drug effects
heliomicin
Hemolymph - chemistry
Hydrophobic and Hydrophilic Interactions
insect immunity
Insect Proteins - chemistry
Insect Proteins - isolation & purification
Larva - chemistry
Lepidoptera - chemistry
Microbial Sensitivity Tests
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed - genetics
NMR structure
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Protein Structure, Secondary
Recombinant Proteins - genetics
Recombinant Proteins - isolation & purification
Recombinant Proteins - pharmacology
Scedosporium - drug effects
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Static Electricity
Structural Homology, Protein
Structure-Activity Relationship
Surface Properties
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Summary: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 CSαβ scaffold (an α‐helix linked to a β‐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 CSαβ 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.
ISSN:0961-8368
1469-896X
DOI:10.1110/ps.03404404