Structure-function relationship of king cobra cathelicidin.

Abstract 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 μg/ml vs 8–32 μg/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 μg/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 μg/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 25 mg/kg). Taken together, our results suggested that OH-CATH(5–34) should be considered as an excellent candidate for developing therapeutic drugs.