Tamaki Makoto, Harada Takuji, Fujinuma Kenta, Takanashi Kazumasa, Shindo Mitsuno, Kimura Masahiro, Uchida Yoshiki
Department of Chemistry, Toho University, Funabashi, Chiba 274-8510, Japan.
Chem Pharm Bull (Tokyo). 2012;60(9):1134-8. doi: 10.1248/cpb.c12-00290.
The substitution of each constituent amino acid residue of gramicidin S (GS), cyclo(-Val(1,1')-Orn(2,2')-Leu(3,3')-D-Phe(4,4')-Pro(5,5')-)(2) with Lys residue indicated that each side chain structure of the constituent amino acid residues affect largely the antibiotic activity and hemolytic activity of GS. Further, the substitution of D-Phe(4,4') and Pro(5,5') residues with basic amino acid residues as a Lys residue results the high antibiotic activity and the very low hemolytic activity. Thus, we have found novel positions on the scaffold of GS at D-Phe(4,4') and Pro(5,5') residues whose modification will significantly increase the therapeutic index.
用赖氨酸残基取代短杆菌肽S（GS），环（-缬氨酸（1,1'）-鸟氨酸（2,2'）-亮氨酸（3,3'）-D-苯丙氨酸（4,4'）-脯氨酸（5,5'）-）（2）的每个组成氨基酸残基，表明组成氨基酸残基的每个侧链结构在很大程度上影响GS的抗生素活性和溶血活性。此外，用碱性氨基酸残基如赖氨酸残基取代D-苯丙氨酸（4,4'）和脯氨酸（5,5'）残基会导致高抗生素活性和极低的溶血活性。因此，我们在GS支架上的D-苯丙氨酸（4,4'）和脯氨酸（5,5'）残基上发现了新的位点，对其进行修饰将显著提高治疗指数。
