Potent inhibition of the classical pathway of complement by a novel C1q-binding peptide derived from the human astrovirus coat protein
Potent inhibition of the classical pathway of complement by a novel C1q-binding peptide derived from the human astrovirus coat protein
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DOI：
10.1016/j.molimm.2010.07.012
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发表时间：
2010-11-01
影响因子：
3.6
通讯作者：
Krishna, Neel K.
中科院分区：
文献类型：
--
作者：
Gronemus, Jenny Q.;Hair, Pamela S.;Krishna, Neel K.
我们实验室之前的研究表明，纯化的重组人星状病毒衣壳蛋白（HAstV CP）结合C1q和甘露糖结合凝集素（MBL），分别抑制补体经典和凝集素途径的激活。对787个氨基酸CP分子的分析表明，残基79-139与人中性粒细胞防御素-1 （HNP-1）具有有限的序列同源性，HNP-1先前被证明结合C1q和MBL，抑制经典和团队的激活从CP分子的这一区域衍生的一个30个氨基酸的肽竞争性地抑制野生型CP与C1q的结合，随后在溶血实验中测定了亲本肽和各种衍生物对C1q结合抑制C1和C4的激活以及对补体激活的抑制。在这些功能分析中，亲本肽和几种衍生物在不同程度上抑制补体激活，特别是一种肽衍生物（E23A）在经典补体途径激活的多个测试中表现出优越的补体激活抑制作用。进一步的分析显示，它与植物防御素具有同源性，从而建立了E23A的结构模型。基于这些发现，我们假设进一步优化E23A的基本原理可能会导致a有前景的治疗抑制剂，用于治疗炎性和自身免疫性疾病，其中补体经典和凝集素途径激活失调导致发病机制(C) 2010 Elsevier Ltd版权所有
Previous work from our laboratories has demonstrated that purified recombinant human astrovirus coat protein (HAstV CP) binds C1q and mannose-binding lectin (MBL) inhibiting activation of the classical and lectin pathways of complement respectively Analysis of the 787 amino acid CP molecule revealed that residues 79-139 share limited sequence homology with human neutrophil defensin-1 (HNP-1) a molecule previously demonstrated to bind C1q and MBL inhibiting activation of the classical and team pathways of complement respectively A 30 amino acid peptide derived from this region of the CP molecule competitively inhibited the binding of wild-type CP to C1q The parent peptide and various derivatives were subsequently assayed for C1q binding inhibition of C1 and C4 activation as well as suppression of complement activation in hemolytic assay, The parent peptide and several derivatives inhibited complement activation in these functional assays to varying degrees One peptide derivative in particular (E23A) displayed superior inhibition of complement activation in multiple assays of classical complement pathway activation Further analysis revealed homology to a plant defensin allowing development of a proposed structural model for E23A Based upon these findings we hypothesize that further rationale optimization of E23A may result in a promising therapeutic inhibitor for the treatment of inflammatory and autoimmune diseases in which dysregulated activation of the classical and lectin pathways of complement contribute to pathogenesis (C) 2010 Elsevier Ltd All rights reserved