Structure-function relationship of king cobra cathelicidin.
King cobra cathelicidin (OH-CATH) is composed of 34 amino acid residues having strong antibacterial and very weak hemolytic activities as reported by us recently. OH-CATH can be served as a valuable template to develop novel therapeutic drugs. In this study, OH-CATH and six of its analogs were synthesized to explore their structure-function relationships based on their bactericidal and hemolytic activities. Experimental results of OH-CATH(3-34) and OH-CATH(5-34) indicated that the N-terminal 4 amino acid residues of OH-CATH played an important role on its hemolytic activity but had weak effects on its bactericidal activity. Among OH-CATH and its analogs, OH-CATH(5-34) had the lowest hemolytic activity while maintained strong antimicrobial activity. To evaluate its potential usage, the biological activities of OH-CATH(5-34) were compared with those of pexiganan. The bactericidal activity of OH-CATH(5-34) against 5 different species (11 laboratory strains) was 2-4 times stronger than that of pexiganan (4-16 microg/ml vs 8-32 microg/ml). Hemolytic activity of OH-CATH(5-34) against human erythrocytes was 0.69% while that of pexiganan was 16.5% at the dosage of 200 microg/ml. OH-CATH(5-34) showed very weak cytotoxic activities against primary rabbit ventricular endothelial cells and four human cancer cell lines whereas pexiganan showed strong cytotoxic activity against these five cell lines (IC(50)=20-90 microg/ml). The intravenous LD(50) value of OH-CATH(5-34) on mice was 7-fold higher than that of pexiganan (175 mg/kg vs 25mg/kg). Taken together, our results suggested that OH-CATH(5-34) should be considered as an excellent candidate for developing therapeutic drugs.
Zhang
Yong
Y
Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
Zhao
Hui
H
Yu
Guo-Yu
GY
Liu
Xiao-Dong
XD
Shen
Ji-Hong
JH
Lee
Wen-Hui
WH
Zhang
Yun
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054804:Cathelicidins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015195:Drug Design; D017815:Elapidae / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000302:isolation & purification; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000302:isolation & purification; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D030162:Reptilian Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D054804:Cathelicidins; D010446:Peptide Fragments; D030162:Reptilian Proteins; C093828:pexiganan