Identification of Allosteric Peptide Agonists of CXCR4*
Identification of Allosteric Peptide Agonists of CXCR4*
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DOI：
10.1074/jbc.m204667200
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发表时间：
2003-01
期刊：
影响因子：
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通讯作者：
A. Sachpatzidis;B. Benton;J. Manfredi;Huan Wang;A. Hamilton;H. Dohlman;E. Lolis
中科院分区：
文献类型：
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作者：
A. Sachpatzidis;B. Benton;J. Manfredi;Huan Wang;A. Hamilton;H. Dohlman;E. Lolis
趋化因子受体CXCR 4是HIV-1嗜T型毒株的共受体。许多CXCR 4的小分子拮抗剂正在开发中，但由于CXCR 4的生理功能，所有这些拮抗剂都可能导致不良反应。为了预防这些并发症，变构激动剂可以与小分子拮抗剂组合作为辅助疗法在治疗上有用。在表达功能性受体的酵母菌株中筛选编码160，000种不同SDF基肽的合成cDNA文库的CXCR 4激动剂活性。以自分泌方式激活CXCR 4的肽诱导集落形成。两种肽，命名为RSVM和ASLW，被鉴定为对CXCR 4拮抗剂AMD 3100不敏感的新型激动剂。在使用急性淋巴细胞白血病细胞系CCRF-CEM的趋化性测定中，RSVM表现为部分激动剂，ASLW表现为超激动剂。ASLW的超激动剂活性可能与其不能诱导受体内化有关。在CCRF-CEM细胞中，这两种肽也不被另一种CXCR 4拮抗剂T140或中和性单克隆抗体12 G5和44717.111抑制。这些结果表明，替代激动剂结合位点存在于CXCR 4上，可以筛选以开发用于治疗用途的分子。
The chemokine receptor CXCR4 is a co-receptor for T-tropic strains of HIV-1. A number of small molecule antagonists of CXCR4 are in development but all are likely to lead to adverse effects due to the physiological function of CXCR4. To prevent these complications, allosteric agonists may be therapeutically useful as adjuvant therapy in combination with small molecule antagonists. A synthetic cDNA library coding for 160,000 different SDF-based peptides was screened for CXCR4 agonist activity in a yeast strain expressing a functional receptor. Peptides that activated CXCR4 in an autocrine manner induced colony formation. Two peptides, designated RSVM and ASLW, were identified as novel agonists that are insensitive to the CXCR4 antagonist AMD3100. In chemotaxis assays using the acute lymphoblastic leukemia cell line CCRF-CEM, RSVM behaves as a partial agonist and ASLW as a superagonist. The superagonist activity of ASLW may be related to its inability to induce receptor internalization. In CCRF-CEM cells, the two peptides are also not inhibited by another CXCR4 antagonist, T140, or the neutralizing monoclonal antibodies 12G5 and 44717.111. These results suggest that alternative agonist-binding sites are present on CXCR4 that could be screened to develop molecules for therapeutic use.