Characteristics of novel insect defensin-based membrane-disrupting trypanocidal peptides.
Synthetic D- and L-amino acid type cationic 9-mer peptides (all sequences were synthesized as D- or L-amino acids) derived from the active sites of insect defensins were tested for their ability to modify the growth of blood-stream form African trypanosomes in vitro. One of them, the D-type peptide A (RLYLRIGRR-NH(2)), irreversibly suppressed proliferation of the Trypanosoma brucei brucei GUTat3.1 parasite. The presence of negatively charged phosphatidylserine on the surface of the parasites was demonstrated, suggesting electrostatic interaction between the peptide and the phospholipids. Furthermore, this peptide was found to alter trypanosome membrane-potentials significantly, an effect apparently due to the removal of the parasite's plasma membrane. The potential toxic effects of D-peptide A on mammalian cells was assessed using human brain microvascular endothelial cells. Only minor effects were found when the endothelial cells were exposed for 16 h to peptide concentrations of less than 200 microM. These findings suggest that insect defensin-based peptides represent a potentially new class of membrane-disrupting trypanocidal drugs.
Yamage
Mat
M
Innate Immunity Research Unit, National Institute of the Agrobiological Sciences, Tsukuba, Ibaraki, Japan.
Yoshiyama
Mikio
M
Grab
Dennis J
DJ
Kubo
Masanori
M
Iwasaki
Takashi
T
Kitani
Hiroshi
H
Ishibashi
Jun
J
Yamakawa
Minoru
M
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000098:blood supply; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D023082:Defensins / Q000737:chemistry*; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D019476:Insect Proteins / Q000737:chemistry*; D008564:Membrane Potentials / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D055806:Microvessels / Q000166:cytology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010743:Phospholipids / Q000378:metabolism; D013237:Stereoisomerism; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure
D023082:Defensins; D019476:Insect Proteins; D009842:Oligopeptides; D010743:Phospholipids; D014344:Trypanocidal Agents