Structural determinants for the membrane interaction of novel bioactive undecapeptides derived from gaegurin 5.
Gaegurin 5 is a 24-residue, membrane-active antimicrobial peptide isolated from the skin of an Asian frog, Rana rugosa. We recently reported the antimicrobial activities of two novel undecapeptides derived from an inactive N-terminal fragment (residues 1-11) of gaegurin 5 (Won, et al. J. Biol. Chem. 2004, 279, 14784-14791). In the present work, the anticancer activities of the two antimicrobial undecapeptide analogues were additionally identified. The relationships between their structural properties and biological activities were assessed by characterizing the fundamental structural determinant for the basic membrane interaction. The circular dichroism and nuclear magnetic resonance results revealed that in a membrane-mimetic environment, the active peptides adopt a more stabilized helical conformation than that of the inactive fragment, and this conformation conferred an overall amphipathicity to the active peptides. Therefore, the most decisive factor responsible for the activity and selectivity could be the intramolecular amphipathic cooperativity, rather than the amphipathicity itself. Especially, the tryptophan residue of the active peptides seems to play a crucial role at the critical amphipathic interface that promotes and balances the amphipathic cooperativity by stabilizing both the hydrophilic and hydrophobic interactions with the membrane. Altogether, the present results suggest that the two novel undecapeptides are worthy of therapeutic development as new antibiotic and anticancer agents and provide structural information about their action mechanism.
Won
Hyung-Sik
HS
Department of Biotechnology, Division of Life Sciences, College of Biomedical & Health Science, Konkuk University, Chungju, Chungbuk 380-701, Korea.
Seo
Min-Duk
MD
Jung
Seo-Jeong
SJ
Lee
Sang-Jae
SJ
Kang
Su-Jin
SJ
Son
Woo-Sung
WS
Kim
Hyun-Jung
HJ
Park
Tae-Kyu
TK
Park
Sung-Jean
SJ
Lee
Bong-Jin
BJ
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry*; D011498:Protein Precursors / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D009842:Oligopeptides; D010455:Peptides; D011498:Protein Precursors; C096397:gaegurin 5