Design and synthesis of cyclic disulfide-bonded antibacterial peptides on the basis of the alpha helical domain of Tenecin 1, an insect defensin.
We synthesized cyclic disulfide-bonded (i, i+4) peptides with various net positive charges (+2-+5) from linear peptides derived from the alpha helical domain of Tenecin 1, an insect defensin, and investigated the effect of the intradisulfide bridge (i, i+4) on hydrophobicity, secondary structure, leakage activity and binding activity for large unilamellar vesicles, antimicrobial activity, and hemolytic activity. Intradisulfide bridge formation of the peptides resulted in the increase of amphiphilicity and hydrophobicity. Cyclic forms of the peptides did not deeply penetrate into PG/PC (1:1, mole ratio) large unilamellar vesicles and had a decreased lipid membrane perturbation activity for PG/PC LUVs. When the peptides interacted with PG/CL (2:1, mole ratio) LUVs, cyclic peptides with a high net positive charge (+4-+5) showed similar binding affinities and leakage activities for vesicles to those of linear forms, whereas cyclic peptides with a low net positive charge (+2-+3) exhibited lower leakage activity than their linear forms. CD spectra indicate that the intradisulfide bridge (i, i+4) provided little conformational constraint to linear peptides in buffer solution but resulted in the decrease of alpha helicity of the peptides in lipid membrane mimic conditions. The cyclic peptide with the highest net positive charge had a similar antibacterial activity to that of the linear peptide, whereas the cyclic peptides with a low net positive charge (+3-+4) exhibited lower antibacterial activity than their linear forms. The cyclic peptides of an appropriate net charge showed more potent activities against some bacteria than those of linear forms under high salt conditions.
Ahn
Hye-sun
HS
Bioorganic Chemistry Laboratory, Department of Chemistry, Inha University, 253 Younghyun-Dong, Nam-Gu, Inchon-City, 402-751, Republic of Korea.
Cho
Wonmi
W
Kim
Joung-min
JM
Joshi
Bishnu Prasad
BP
Park
Jun-won
JW
Lohani
Chuda Raj
CR
Cho
Hyeongjin
H
Lee
Keun-Hyeung
KH
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002942:Circular Dichroism; D023082:Defensins / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D015195:Drug Design; D019476:Insect Proteins / Q000737:chemistry*; D050296:Microbial Viability / Q000187:drug effects; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D023082:Defensins; D004220:Disulfides; D019476:Insect Proteins; D010456:Peptides, Cyclic