Tamamura H, Arakaki R, Funakoshi H, Imai M, Otaka A, Ibuka T, Nakashima H, Murakami T, Waki M, Matsumoto A, Yamamoto N, Fujii N
Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Bioorg Med Chem. 1998 Feb;6(2):231-8. doi: 10.1016/s0968-0896(97)10037-2.
A tachyplesin peptide analog, T22 ([Tyr5,12, Lys7]-polyphemusin II), and its shortened congener, TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Pro11]-T22) have strong anti-human immunodeficiency virus (HIV) activity, comparable to that of 3'-azido-2', 3'-dideoxythymidine (AZT). T22 and TW70 are extremely basic peptides, containing 5 Arg residues and 3 Lys residues. The number of positive charges might be related in part to high collateral cytotoxicities of T22 and TW70. Here we have synthesized several analogs, in which the number of positive charges has been reduced through amino acid substitutions using Glu or L-citrulline. As a result, several effective compounds have been found which possess higher selectivity indexes (SIs, 50% cytotoxic concentration/50% effective concentration) than those of T22 and TW70. Higher SIs were attributed mainly to a decrease in cytotoxicity.
一种鲎抗菌肽类似物T22（[酪氨酸5,12，赖氨酸7]-鲎素II）及其缩短的同类物TW70（去-[半胱氨酸8,13，酪氨酸9,12]-[D-赖氨酸10，脯氨酸11]-T22）具有很强的抗人类免疫缺陷病毒（HIV）活性，与3'-叠氮-2'，3'-双脱氧胸苷（AZT）相当。T22和TW70是极具碱性的肽，含有5个精氨酸残基和3个赖氨酸残基。正电荷的数量可能部分与T22和TW70的高附带细胞毒性有关。在此，我们合成了几种类似物，其中通过使用谷氨酸或L-瓜氨酸进行氨基酸取代来减少正电荷的数量。结果，发现了几种有效的化合物，它们具有比T22和TW70更高的选择性指数（SI，50%细胞毒性浓度/50%有效浓度）。更高的SI主要归因于细胞毒性的降低。
