Role of positional hydrophobicity in the leishmanicidal activity of magainin 2.
The emergence of membrane-active antimicrobial peptides as new alternatives against pathogens with multiantibiotic resistance requires the design of better analogues. Among the different physicochemical parameters involved in the optimization of linear antimicrobial peptides, positional hydrophobicity has recently been incorporated. This takes into consideration the concept of the topological distribution of hydrophobic residues throughout the sequence rather than the classical concept of hydrophobicity as a global parameter of the peptide, calculated as the summation of the individual hydrophobicities of the residues. In order to assess the contribution of this parameter to the leishmanicidal mechanisms of magainin 2 analogues, the activities of two of these analogues, MG-H1 (GIKKFLHIIWKFIKAFVGEIMNS) and MG-H2 (IIKKFLHSIWKFGKAFVGEIMNI), which have similar charges, amino acid compositions, and hydrophobicities but different positional hydrophobicities, against Leishmania donovani promastigotes were assayed (T. Tachi, R. F. Epand, R. M. Epand, and K. Matsuzaki, Biochemistry 41:10723-10731, 2002). The activities were compared with that of the parental peptide, F5W-magainin 2 (GIGKWLHSAKKFGKAFVGEIMNS). The three peptides were active at micromolar concentrations, in the order MG-H2 > MG-H1 > F5W-magainin 2. These activities differ from their hemolytic and bactericidal activities. The results demonstrate that positional hydrophobicity, which reflects the presence of short stretches of sequences rich in hydrophobic amino acids, plays an important role in the activities of leishmanicidal peptides.
Centro de Investigaciones Biológicas (CSIC), E-28040, Madrid, Spain.
Esther
E
Guerrero
José María
JM
Saugar
Katsumi
K
Matsuzaki
Luis
L
Rivas
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004734:Energy Metabolism; D005470:Fluorometry; D019276:Glycocalyx / Q000737:chemistry; D006461:Hemolysis / Q000187:drug effects; D007202:Indicators and Reagents; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D054806:Magainins; D008564:Membrane Potentials / Q000187:drug effects; D008854:Microscopy, Electron; D010455:Peptides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D029867:Xenopus Proteins / Q000494:pharmacology*; D014982:Xenopus laevis
D023181:Antimicrobial Cationic Peptides; D000981:Antiprotozoal Agents; D007202:Indicators and Reagents; D054806:Magainins; D010455:Peptides; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus; D000255:Adenosine Triphosphate