Structure-activity studies of 14-helical antimicrobial beta-peptides: probing the relationship between conformational stability and antimicrobial potency.
Identifieur interne : 003311 ( Main/Exploration ); précédent : 003310; suivant : 003312Structure-activity studies of 14-helical antimicrobial beta-peptides: probing the relationship between conformational stability and antimicrobial potency.
Auteurs : Tami L. Raguse [États-Unis] ; Emilie A. Porter ; Bernard Weisblum ; Samuel H. GellmanSource :
- Journal of the American Chemical Society [ 0002-7863 ] ; 2002.
Descripteurs français
- KwdFr :
- Antibactériens (), Antibactériens (pharmacologie), Bacillus subtilis (), Conception de médicament, Dichroïsme circulaire, Enterococcus faecalis (), Escherichia coli (), Oligopeptides (), Oligopeptides (pharmacologie), Oligopeptides (synthèse chimique), Relation structure-activité, Stabilité de médicament, Staphylococcus aureus (), Structure secondaire des protéines, Tests de sensibilité microbienne.
- MESH :
- pharmacologie : Antibactériens, Oligopeptides.
- synthèse chimique : Oligopeptides.
- Antibactériens, Bacillus subtilis, Conception de médicament, Dichroïsme circulaire, Enterococcus faecalis, Escherichia coli, Oligopeptides, Relation structure-activité, Stabilité de médicament, Staphylococcus aureus, Structure secondaire des protéines, Tests de sensibilité microbienne.
English descriptors
- KwdEn :
- Anti-Bacterial Agents (chemistry), Anti-Bacterial Agents (pharmacology), Bacillus subtilis (drug effects), Circular Dichroism, Drug Design, Drug Stability, Enterococcus faecalis (drug effects), Escherichia coli (drug effects), Microbial Sensitivity Tests, Oligopeptides (chemical synthesis), Oligopeptides (chemistry), Oligopeptides (pharmacology), Protein Structure, Secondary, Staphylococcus aureus (drug effects), Structure-Activity Relationship.
- MESH :
- chemical , chemical synthesis : Oligopeptides.
- chemical , chemistry : Anti-Bacterial Agents, Oligopeptides.
- chemical , pharmacology : Anti-Bacterial Agents, Oligopeptides.
- drug effects : Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Staphylococcus aureus.
- Circular Dichroism, Drug Design, Drug Stability, Microbial Sensitivity Tests, Protein Structure, Secondary, Structure-Activity Relationship.
Abstract
Antimicrobial alpha-helical alpha-peptides are part of the host-defense mechanism of multicellular organisms and could find therapeutic use against bacteria that are resistant to conventional antibiotics. Recent work from Hamuro et al. has shown that oligomers of beta-amino acids ("beta-peptides") that can adopt an amphiphilic helix defined by 14-membered ring hydrogen bonds ("14-helix") are active against Escherichia coli [Hamuro, Y.; Schneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200-12201]. We have created two series of cationic 9- and 10-residue amphiphilic beta-peptides to probe the effect of 14-helix stability on antimicrobial and hemolytic activity. 14-Helix stability within these series is modulated by varying the proportions of rigid trans-2-aminocyclohexanecarboxylic acid (ACHC) residues and flexible acyclic residues. We have previously shown that a high proportion of ACHC residues in short beta-peptides encourages 14-helical structure in aqueous solution [Appella, D. H.; Barchi, J. J.; Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309-2310]. Circular dichroism of the beta-peptides described here reveals a broad range of 14-helix population in aqueous buffer, but this variation in helical propensity does not lead to significant changes in antibiotic activity against a set of four bacteria. Several of the 9-mers display antibiotic activity comparable to that of a synthetic magainin derivative. Among these 9-mers, hemolytic activity increases slightly with increasing 14-helical propensity, but all of the 9-mers are less hemolytic than the magainin derivative. Previous studies with conventional peptides (alpha-amino acid residues) have provided conflicting evidence on the relationship between helical propensity and antimicrobial activity. This uncertainty has arisen because alpha-helix stability can be varied to only a limited extent among linear alpha-peptides without modifying parameters important for antimicrobial activity (e.g., net charge or hydrophobicity); a much greater range of helical stability is accessible with beta-peptides. For example, it is very rare for a linear alpha-peptide to display significant alpha-helix formation in aqueous solution and manifest antibacterial activity, while the linear beta-peptides described here range from fully unfolded to very highly folded in aqueous solution. This study shows that beta-peptides can be unique tools for analyzing relationships between conformational stability and biological activity.
DOI: 10.1021/ja0270423
PubMed: 12392424
Affiliations:
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Le document en format XML
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<term>Circular Dichroism</term>
<term>Drug Design</term>
<term>Drug Stability</term>
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<term>Dichroïsme circulaire</term>
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<front><div type="abstract" xml:lang="en">Antimicrobial alpha-helical alpha-peptides are part of the host-defense mechanism of multicellular organisms and could find therapeutic use against bacteria that are resistant to conventional antibiotics. Recent work from Hamuro et al. has shown that oligomers of beta-amino acids ("beta-peptides") that can adopt an amphiphilic helix defined by 14-membered ring hydrogen bonds ("14-helix") are active against Escherichia coli [Hamuro, Y.; Schneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200-12201]. We have created two series of cationic 9- and 10-residue amphiphilic beta-peptides to probe the effect of 14-helix stability on antimicrobial and hemolytic activity. 14-Helix stability within these series is modulated by varying the proportions of rigid trans-2-aminocyclohexanecarboxylic acid (ACHC) residues and flexible acyclic residues. We have previously shown that a high proportion of ACHC residues in short beta-peptides encourages 14-helical structure in aqueous solution [Appella, D. H.; Barchi, J. J.; Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309-2310]. Circular dichroism of the beta-peptides described here reveals a broad range of 14-helix population in aqueous buffer, but this variation in helical propensity does not lead to significant changes in antibiotic activity against a set of four bacteria. Several of the 9-mers display antibiotic activity comparable to that of a synthetic magainin derivative. Among these 9-mers, hemolytic activity increases slightly with increasing 14-helical propensity, but all of the 9-mers are less hemolytic than the magainin derivative. Previous studies with conventional peptides (alpha-amino acid residues) have provided conflicting evidence on the relationship between helical propensity and antimicrobial activity. This uncertainty has arisen because alpha-helix stability can be varied to only a limited extent among linear alpha-peptides without modifying parameters important for antimicrobial activity (e.g., net charge or hydrophobicity); a much greater range of helical stability is accessible with beta-peptides. For example, it is very rare for a linear alpha-peptide to display significant alpha-helix formation in aqueous solution and manifest antibacterial activity, while the linear beta-peptides described here range from fully unfolded to very highly folded in aqueous solution. This study shows that beta-peptides can be unique tools for analyzing relationships between conformational stability and biological activity.</div>
</front>
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