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首页> 外文期刊>Biochemistry >Structural Analysis of Immunotherapeutic Peptides for Autoimmune Myasthenia Gravis
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Structural Analysis of Immunotherapeutic Peptides for Autoimmune Myasthenia Gravis

机译：自身免疫性重症肌无力免疫治疗肽的结构分析

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Myasthenia gravis (MG) and its animal model, experimental MG (EAMG), are autoimmune disorders in which major pathogenic antibodies are directed against the main immunogenic region (MIR) of the nicotinic acetylcholine receptor (nAChR). In an earlier attempt to develop peptide mimotopes capable of preventing the anti-MIR-mediated pathogenicity, the peptide Pep.1 was initially identified from phage display, and subsequently, Cyclic extended Pep.1 (Cyc.ext.Pep.1), which incorporates eight additional residues into the Pep.1 sequence and has an affinity for the anti-MIR antibody mAb198 3 orders of magnitude greater than that of Pep.1, was developed. In an animal model, Pep.1 shows no ability to inhibit mAb198-induced EAMG, whereas Cyc.ext.Pep.1 successfully blocks anti-MIR antibody 198 (mAb198)-induced EAMG. Our aim in this study was to identify the structural characteristics related to the different affinities for mAb198 of Pep.1 and Cyc.ext.Pep.1 using NMR spectroscopy and alanine scanning analysis. The NMR structural analysis revealed that Pep.1 is very flexible in solution, whereas Cyc.ext.Pep.1 is highly rigid within a region containing several turn structures. Interestingly, TRNOE experiments revealed that mAb198-bound Pep.1, particularly in the region between Asn7 and Glu11, shows significant structural similarity to the region between Asn10 and Glu14 of Cyc.ext.Pep.1, which is critical for interaction with mAb198. We therefore conclude the higher affinity of Cyc.ext.Pep.1 for mAb198 reflects the fact that incorporation of additional residues producing a single disulfide bond endows Pep.1 with a conformational rigidity that mimics the structure of mAb198-bound Pep. 1. Furthermore, our results suggest that cyclic extended peptides could be utilized generally as useful tools to optimize the affinity of phage library-derived peptide antigens.
机译：重症肌无力（MG）及其动物模型实验性MG（EAMG）是自身免疫性疾病，其中主要的病原性抗体针对烟碱乙酰胆碱受体（nAChR）的主要免疫原性区域（MIR）。在开发能够预防抗MIR介导的致病性的肽模拟表位的较早尝试中，最初从噬菌体展示中鉴定出了肽Pep.1，随后从环状延伸的Pep.1（Cyc.ext.Pep.1）中鉴定了该肽。已开发出在Pep.1序列中整合了八个额外残基，并且对抗MIR抗体mAb198的亲和力比Pep.1大3个数量级。在动物模型中，Pep.1没有抑制mAb198诱导的EAMG的能力，而Cyc.ext.Pep.1成功地阻断了抗MIR抗体198（mAb198）诱导的EAMG。我们在这项研究中的目的是使用NMR光谱法和丙氨酸扫描分析法确定与Pep.1和Cyc.ext.Pep.1的mAb198不同亲和力相关的结构特征。 NMR结构分析表明，Pep.1在溶液中非常柔软，而Cyc.ext.Pep.1在包含多个匝结构的区域内具有很高的刚性。有趣的是，TRNOE实验表明，mAb198结合的Pep.1，特别是在Asn7和Glu11之间的区域，与Cyc.ext.Pep.1的Asn10和Glu14之间的区域具有明显的结构相似性，这对于与mAb198的相互作用至关重要。因此，我们得出结论，Cyc.ext.Pep.1对mAb198的更高亲和力反映了以下事实：掺入产生单个二硫键的其他残基赋予Pep.1具有模仿mAb198结合的Pep结构的构象刚度。 1.此外，我们的结果表明，环状延伸肽通常可以用作优化噬菌体库衍生肽抗原亲和力的有用工具。

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