Selective inhibition of N-formylpeptide-induced neutrophil activation by carbamate-modified peptide analogues
Selective inhibition of N-formylpeptide-induced neutrophil activation by carbamate-modified peptide analogues
复制标题
DOI：
10.1021/bi952087k
复制
发表时间：
1996-01-30
期刊：
影响因子：
2.9
通讯作者：
Fischman, AJ
中科院分区：
文献类型：
--
作者：
Derian, CK;Solomon, HF;Fischman, AJ
白细胞N-甲酰肽受体（FPR）的刺激诱导趋化性、细胞粘附、自由基释放和脱粒，这些反应与感染和炎症相关。在受体持续激活的条件下，嗜中性粒细胞依赖性组织损伤增强。FPR的拮抗剂具有用作诊断和治疗剂的潜力。因此，我们已经合成和评估了一系列的氨基末端氨基甲酸酯类似物的肽Met-Leu-Phe（MLF），以确定在人中性粒细胞FPR赋予激动剂或拮抗剂活性的结构要求，肽进行了评估，在三个体外试验：受体结合，超氧阴离子释放，和细胞粘附。未支化的氨基甲酸酯（甲氧羰基，乙氧羰基和正丁氧基羰基）导致激动剂活性，而支化的氨基甲酸酯（异丁氧基羰基，叔丁氧基羰基和苄氧基羰基）是拮抗剂。肽拮抗剂是更有效的抑制超氧阴离子释放比细胞粘附的4-7倍。当异丁氧羰基-MLF（i-Boc-MLF）在羧基末端用赖氨酸进一步修饰时，保留了拮抗剂效力，但没有功能选择性。用放射性核素连接体二亚乙基三胺五乙酸进一步修饰C-末端不会改变i-Boc-MLFK的效力。这些结果表明，从激动剂到拮抗剂活性的转换可以通过修饰氨基末端基团的总体大小和形状来实现;氨基和羧基末端的修饰可以改变肽的功能选择性;羧基末端的修饰可以耐受，以允许开发用于诊断应用的拮抗剂。
Stimulation Of the leukocyte N-formylpeptide receptor (FPR) induces chemotaxis, cell adhesion, free radical release, and degranulation, responses associated with infection and inflammation. Under conditions where continuous activation of the receptor prevails, neutrophil-dependent tissue damage ensues. Antagonists of the FPR have potential for use as diagnostic and therapeutic agents. Hence, we have synthesized and evaluated a series of amino-terminal carbamate analogues of the peptide Met-Leu-Phe (MLF) in order to determine the structural requirements for imparting agonist or antagonist activity at the human neutrophil FPR, Peptides were evaluated in three in vitro assays: receptor binding, superoxide anion release, and cell adhesion. Unbranched carbamates (methoxycarbonyl, ethoxycarbonyl, and n-butyloxycarbonyl) resulted in agonist activity, whereas branched carbamates (iso-butyloxycarbonyl, tert-butyloxycarbonyl, and benzyloxycarbonyl) were antagonists. The peptide antagonists were more potent inhibitors of superoxide anion release than cell adhesion by 4-7-fold. When iso-butyloxycarbonyl-MLF (i-Boc-MLF) was further modified at the carboxy terminus with Lys, antagonist potency was retained but without functional selectivity. Further C-terminal modification with the radionuclide linker diethylenetriaminepentaacetic acid did not alter the potency of i-Boc-MLFK. These results indicate that the switch from agonist to antagonist activity can be achieved by modifying the overall size and shape of the aminoterminal group; that modifications at both the amino and carboxy termini can alter the functional selectivity of the peptide; and that modifications can be tolerated at the carboxy terminus to allow for development of an antagonist for diagnostic applications.