Retro and Retroenantio Analogs of Cecropin-Melittin Hybrids

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 8; pp. 3449 - 3453
• Main Authors: Merrifield, R. B., Juvvadi, Padmaja, Andreu, David, Ubach, Josep, Boman, Anita, Boman, Hans G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 11.04.1995; National Acad Sciences; National Academy of Sciences
• Subjects: Amides; Amino Acid Sequence; Amino acids; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterials; Antimicrobial Cationic Peptides; Artificial membranes; Biochemistry; Chirality; Circular Dichroism; Ellipticity; Hemolysis; Immunity (Disease); Isomers; Melitten - chemistry; Melitten - genetics; Melitten - pharmacology; Microbial Sensitivity Tests; Molecular Sequence Data; Protein Conformation; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - pharmacology; Stereoisomerism; Structure-Activity Relationship; Teeth; Topology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.8.3449

Hybrid analogs of cecropin A (CA) and melittin (M), which are potent antibacterial peptides, have been synthesized. To understand the structural requirements for this antibacterial activity, we have also synthesized the enantio, retro, and retroenantio isomers of two of the hybrids and their N-terminally acetylated derivatives. All analogs of CA(1-13)M(1-13)-NH2were as active as the parent peptide against five test bacterial strains, but one bacterial strain was resistant to the retro and retroenantio derivatives. Similarly, all analogs of CA(1-7)M(2-9)-NH2were active against four strains, while two strains were resistant to the retro and retroenantio analogs containing free NH+ 3end groups, but acetylation restored activity against one of them. From these data it was concluded that chirality of the peptide was not a critical feature, and full activity could be achieved with peptides containing either all L- or all D-amino acids in their respective right-handed or left-handed helical conformations. For most of the bacterial strains, the sequence of these peptides or the direction of the peptide bonds could be critical but not both at the same time. For some strains, both needed to be conserved.