Enhancing the hypotensive effect and diminishing the cytolytic activity of hornet mastoparan B by D-amino acid substitution.
Mastoparan B (MP-B) is a cationic tetradecapeptide (LKLKSIVSWAKKVL-CONH(2)) isolated from the venom of the Taiwan hornet Vespa basalis. Unlike other vespid mastoparans, the peptide is capable of inducing short-term hypotension and causes hemolysis in animals. This study was aimed to find out MP-B analogs that possess higher hypotensive potency with the least lytic action by D-amino acid substitution, especially at lysine (Lys) residues. The synthetic MP-B isomer in which Lys(2) was replaced by D-Lys showed a significant decrease in both hemolytic and hypotensive activities. Substitution of Lys(4) by D-Lys in MP-B also caused a marked reduction of hemolytic activity, but its hypotensive action was only slightly affected. However, when Lys(11,12) were replaced by D-Lys, the resulting isomer ([D-Lys(11,12)]MP-B) exhibited a higher hypotensive activity with negligible hemolytic activity as compared with the native peptide. The D-antipot of MP-B in which all amino acid residues were replaced by D-isomers showed the highest hypotensive activity with a hemolytic activity about 1/5 that of MP-B. The results reveal that D-Lys substitution at the N-terminus of MP-B (Lys(2,4)) causes decreases in both hypotensive and hemolytic activities, while D-Lys substitution at the C-terminus (Lys(11,12)) leads to a significant increase in hypotensive activity of MP-B with a remarkable decrease in hemolytic activity. The hypotensive effect of [D-Lys(11,12)]MP-B was more prominent on spontaneously hypertensive rats. At a proper dose (0.3mg/kg) the peptide could reduce the high blood pressure (approximately 180 mmHg) of the rat to a normal level (approximately 120 mmHg) for more than 3h. [D-Lys(11,12)]MP-B which possesses a potent hypotensive action with the least cytolytic side effect is the best MP-B analog for studying the mechanism of cardiovascular inhibition by MP-B and could be useful as a hypotensive agent in hypertension crisis.
Ho
C L
CL
Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan.
Shih
Y P
YP
Wang
K T
KT
Yu
H M
HM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects*; D006168:Guinea Pigs; D006461:Hemolysis / Q000187:drug effects*; D007022:Hypotension / Q000188:drug therapy*; D036341:Intercellular Signaling Peptides and Proteins; D008239:Lysine / Q000737:chemistry*; D008297:Male; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000302:isolation & purification / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014862:Wasp Venoms / Q000737:chemistry* / Q000302:isolation & purification; D014863:Wasps
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D014862:Wasp Venoms; C081223:mastoparan B; D008239:Lysine