Molecular-size reduction of a potent CXCR4-chemokine antagonist using orthogonal combination of conformation- and sequence-based libraries
Molecular-size reduction of a potent CXCR4-chemokine antagonist using orthogonal combination of conformation- and sequence-based libraries
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DOI：
10.1002/anie.200351024
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发表时间：
2003-01-01
影响因子：
16.6
通讯作者：
Peiper, SC
中科院分区：
文献类型：
--
作者：
Fujii, N;Oishi, S;Peiper, SC
由基因组科学的最新进展提供的关于天然配体的可用信息呈指数级增长，并放大了药物化学家开发新药的机会。[1]从天然配体中合理设计激动剂/拮抗剂是药物发现的最有效方法之一，同时需要开发创新方法来促进这一过程。在此，我们报告了一种新的策略，使用两个正交的小文库的环肽，这使我们能够确定一种新的CXCR 4拮抗剂等效的亲本肽的生物活性肽的缩小。[2]We T140 [3]是CXCR 4-趋化因子受体的高效特异性拮抗剂，其与HIV-1感染、癌症转移、类风湿性关节炎和慢性淋巴细胞性B细胞白血病相关。[4]T140由14个氨基酸残基和Cys 4和Cys 13之间的一个二硫键组成，我们对T140的结构-活性关系的研究表明，四个不可缺少的氨基酸残基Arg 2，Nal 3，Tyr 5和Arg 14负责其内在生物活性（方案1）。[3a]此外，NMR
The information available on natural ligands provided by recent advances in genome science is exponentially increasing and amplifies the opportunities for medicinal chemists to develop novel pharmaceuticals.[1] Rational drug design of agonists/antagonists from natural ligands offers one of the most powerful methodologies for drug discovery, while development of innovative methods is required to facilitate the processes. Herein, we report a new strategy for the downsizing of bioactive peptides using two orthogonal small libraries of cyclic peptides, which allowed us to identify a novel CXCR4 antagonist equipotent to the parent peptide.[2]We previously reported that T140 [3] is a highly potent specific antagonist of the CXCR4-chemokine receptor, which is relevant to HIV-1 infection, cancer metastasis, rheumatoid arthritis, and chronic lymphocytic B-cell leukemia.[4] Our structure–activity relationship studies on T140, which consists of 14 amino acid residues and one disulfide bridge between Cys 4 and Cys 13, have revealed that four indispensable amino acid residues, Arg2, Nal3, Tyr5, and Arg14, are responsible for its intrinsic bioactivity (Scheme 1).[3a] In addition, NMR