Tamamura H, Imai M, Ishihara T, Masuda M, Funakoshi H, Oyake H, Murakami T, Arakaki R, Nakashima H, Otaka A, Ibuka T, Waki M, Matsumoto A, Yamamoto N, Fujii N
Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Bioorg Med Chem. 1998 Jul;6(7):1033-41. doi: 10.1016/s0968-0896(98)00061-3.
We have previously found that T22 ([Tyr(5,12), Lys7]-polyphemusin II) has strong anti-human immunodeficiency virus (HIV) activity, and that T22 inhibits T cell-line-tropic HIV-1 infection mediated by CXCR4/fusin. T22 is an 18-residue peptide amide, which takes an antiparallel beta-sheet structure that is maintained by two disulfide bridges. Structure-activity relationship (SAR) studies on T22 have disclosed the contributions of each region of T22 to activity or cytotoxicity, and have provided the following useful information to develop new CXCR4 antagonists: The number of Arg residues in the N-terminal and C-terminal regions of T22 is closely related to anti-HIV activity. Addition of a variety of functional groups at the N-terminal end results in increases in activity. Disulfide rings, especially the major disulfide loop, are indispensable for anti-HIV activity and maintenance of the beta-sheet structure. Trp3 can be replaced by other aromatic residues (Tyr, Phe and L-2-naphthylalanine). Between two repeats of Tyr-Arg-Lys, which are a characteristic structure in T22, Tyr-Arg-Lys in the N-terminal portion is more closely associated with anti-HIV activity and maintenance of the beta-sheet structure. A positive charge in the side chain at the (i + 1) position of the beta-turn region is necessary for strong activity. Through these studies, we have found several compounds having higher selectivity indexes (50% cytotoxic concentration/50% effective concentration) than that of T22.
我们之前发现，T22（[酪氨酸(5,12)，赖氨酸7]-海胆精蛋白II）具有很强的抗人类免疫缺陷病毒（HIV）活性，并且T22可抑制由CXCR4/融合素介导的T细胞系嗜性HIV-1感染。T22是一种由18个氨基酸残基组成的肽酰胺，呈反平行β-折叠结构，由两个二硫键维持。对T22的构效关系（SAR）研究揭示了T22各个区域对活性或细胞毒性的贡献，并为开发新的CXCR4拮抗剂提供了以下有用信息：T22 N端和C端区域的精氨酸残基数量与抗HIV活性密切相关。在N端添加各种官能团会导致活性增加。二硫键环，尤其是主要的二硫键环，对于抗HIV活性和β-折叠结构的维持是不可或缺的。色氨酸3可以被其他芳香族残基（酪氨酸、苯丙氨酸和L-2-萘丙氨酸）取代。在T22的特征结构酪氨酸-精氨酸-赖氨酸的两个重复序列之间，N端部分的酪氨酸-精氨酸-赖氨酸与抗HIV活性和β-折叠结构的维持更密切相关。β-转角区域（i + 1）位侧链上的正电荷对于强活性是必需的。通过这些研究，我们发现了几种选择性指数（50%细胞毒性浓度/50%有效浓度）比T22更高的化合物。
