Cell selectivity of an antimicrobial peptide melittin diastereomer with D-amino acid in the leucine zipper sequence.
Melittin (ME), a linear 26-residue non-cell-selective antimicrobial peptide, displays strong lytic activity against bacterial and human red blood cells. To design ME analogue with improved cell selectivity, we synthesized a melittin diastereomer (ME-D) with D-amino acid in the leucine zipper sequence (Leu-6, Lue-13 and Ile-20). Compared to ME, ME-D exhibited the same or 2-fold higher antibacterial activity but 8-fold less hemolytic activity. Circular dichroism analysis revealed that ME-D has much less alpha-helical content in alpha-helical content in the presence of zwitterionic EYPC/cholesterol (10 : 1, w/w) liposomes compared to negatively charged EYPE/EYPG (7 : 3, w/w) liposomes. The blue shift of the fluorescence emission maximum of ME-D in zwitterionic EYPC/ cholesterol (10 : 1, w/w) liposomes was much smaller than in negatively charged EYPE/EYPG (7 : 3, w/w) liposomes. These results suggested that the improvement in therapeutic index/cell selectivity of ME-D is correlated with its less permeability to zwitterionic membranes.
Department of Bio-Materials, Graduate School, Chosun University, Gwangju 501-759, Korea.
Wan Long
WL
Zhu
Yong Hai
YH
Nan
Kyung-Soo
KS
Hahm
Song Yub
SY
Shin
D000595:Amino Acid Sequence; D001419:Bacteria / Q000187:drug effects; D002942:Circular Dichroism; D015195:Drug Design; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D016350:Leucine Zippers / Q000235:genetics; D008555:Melitten / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D013237:Stereoisomerism
D008555:Melitten