Differential activities of decapeptide agonists of human C5a:: the conformational effects of backbone N-methylation
Differential activities of decapeptide agonists of human C5a:: the conformational effects of backbone N-methylation
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DOI：
10.1016/s1567-5769(01)00141-2
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发表时间：
2001-11-01
影响因子：
5.6
通讯作者：
Sanderson, SD
中科院分区：
文献类型：
--
作者：
Vogen, SM;Paczkowski, NJ;Sanderson, SD
合成了人C5a过敏性毒素十肽激动剂C5a(65-74)Y65，F67，P69，P71，D-Ala73(YSFKPMPLaR，肽54)的类似物，其中甲基占据了特定的C5a，酰胺氮原子。这种N-甲基化以类似于两个Pro残基的方式诱导了关键的延伸骨架构象，但没有消除被Pro取代的残基的侧链所作的贡献。多肽54类似物上主链N-甲基的存在对人中性粒细胞上表达的C5aRs的结合和激活能力有显著的不利影响，但对人脐动脉平滑肌的收缩能力没有显著影响。多肽54的几个N甲基化类似物(多肽56、67、124、125和137)对由组织驻留巨噬细胞介导的平滑肌收缩的选择性显著高于对中性粒细胞释放酶的选择性。事实上，多肽67，YSFKDMP(MEL)AR对平滑肌收缩的选择性几乎是PMN酶释放的3000倍。与这些不同的活性一致的是，观察到多肽67与大鼠巨噬细胞上表达的C5aRs的结合亲和力显著高于大鼠PMN上的结合亲和力。在大鼠体内也观察到了这种不同的活性，其中67肽引起了类似于54肽和rhuC5a的降压反应，但没有伴随中性粒细胞减少。(C)2001 Elsevier Science B.V.保留所有权利。
Analogues of the potent, conformationally biased, decapeptide agonist of human C5a anaphylatoxin, C5a(65-74)Y65,F67,P69,P71,D-Ala73 (YSFKPMPLaR, peptide 54), were synthesized with methyl groups occupying specific C5a,, amide nitrogen atoms along the peptide backbone. This N-methylation induced crucial extended backbone conformations in a manner similar to the two Pro residues, but without eliminating the contributions made by the side-chain of the residue for which Pro was substituted. The presence of backbone N-methyl groups on peptide 54 analogues had pronounced detrimental effects on the ability to bind and activate C5aRs expressed on human PMNs, but not on the ability to contract smooth muscle of human umbilical artery. Several N-methylated analogues of peptide 54 (peptides 56, 67, 124, 125, and 137) were significantly more selective for smooth muscle contraction, which is mediated by tissue resident macrophages, than for enzyme release from PMNs. Indeed, peptide 67, YSFKDMP(MeL)aR was almost 3000-fold more selective for smooth muscle contraction than for PMN enzyme release. Consistent with these differential activities was the observation that peptide 67 expressed a significantly greater binding affinity to C5aRs expressed on rat macrophages than on rat PMNs. This differential activity was also observed in vivo in the rat where peptide 67 induced a hypotensive response similar to peptide 54 and rhuC5a, but without accompanying neutropenia. (C) 2001 Elsevier Science B.V. All rights reserved.