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-CONH2) 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 (0.3 mg/kg) the peptide could reduce the high blood pressure (similar to 180 mm Hg) of the rat to a normal level (similar to 120 mm Hg) for more than 3 h. [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. (C) 2001 Elsevier Science Ltd. All rights reserved.