Yoshiki Uchida

Syntheses of low-hemolytic antimicrobial gratisin peptides

Antibiotic and hemolytic activities of gratisin (GR), cyclo(-Val(1)-Orn(2)-Leu(3)-d-Phe(4)-Pro(5)-d-Tyr(6)-)(2), and fifteen GR analogues, which have various d-amino acid residues in place of d-Tyr(6,6) residues, were examined. Among them, [d-Orn(6,6)]-GR, [d-Lys(6,6)]-GR and [d-Arg(6,6)]-GR showed the strong activity against both Gram-positive and Gram-negative bacteria. In addition, the antibiotics showed significantly reduced toxicity against human blood cells compared with gramicidin S, cyclo(-Val(1)-Orn(2)-Leu(3)-d-Phe(4)-Pro(5)-)(2).

Novel gratisin derivatives with high antimicrobial activity and low hemolytic activity.

The substitution of each constituent amino acid residue of gratisin (GR) with Ala residue indicated that each side chain structure of the constituent amino acid residues affect largely the antibiotic and hemolytic activities of GR. Among them, the substitution of Pro residues at positions 5 and 5 with a cationic amino acid residues (Lys and Arg) results the high antibiotic activity and the low toxicity against human blood cells. Thus, we have found a novel position on the scaffold of GR at Pro(5,5) residues whose modification will significantly lower the unwanted hemolytic activity and enhance the desired antibiotic activity.

Fatty acyl-gramicidin S derivatives with both high antibiotic activity and low hemolytic activity

In the present study, novel eight GS derivatives having the octanoyl-(Lys)(n)- moieties, cyclo{-Val-Orn-Leu-d-Phe-Pro(4β-NH-X)-Val-Orn-Leu-d-Phe-Pro-} {X=-H (1), and -(Lys)(n)-CO(CH(2))(6)CH(3)n=0 (2), 1 (3), 2 (4), and 3 (5)} and cyclo{-Val-Orn-Leu-d-Phe-Pro(4α-NH-X)-Val-Orn-Leu-d-Phe-Pro-} {X=-H (6), and -(Lys)(n)-CO(CH(2))(6)CH(3)n=1 (7), and 2 (8)} were synthesized. Among them, 4, 5 and 8 result the high antibiotic activity against both Gram-positive and Gram-negative microorganisms tested. In addition, 4 and 5 showed very low hemolytic activity compared with that of GS. Thus, the introduction of the excess amino groups and the fatty acyl moiety to the γ-NH(2) group of Pro(5) residue in GS molecule lowered the unwanted hemolytic activity and enhanced the desired antibiotic activity.

Phytochelatins inhibit the metal-induced aggregation of α-crystallin

Phytochelatins (PCs) are heavy-metal-binding peptides found in some eukaryotes. This study investigates the use of plant-derived PCs for the inhibition of metal-induced protein aggregation. The results of this study show that PCs inhibit zinc-induced alpha-crystallin aggregation, and suggest that PCs might be useful as anti-cataract agents.