Chen Yi, Shao Shuai, Huang Jingjing, Gu Yuan, Cheng Yuli, Zhu Xinping
Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Front Microbiol. 2020 Dec 23;11:608380. doi: 10.3389/fmicb.2020.608380. eCollection 2020.
Helminth-derived molecules have the ability to modulate the host immune system. Our previous study identified a tetradecapeptide derived from paramyosin (-pmy) that could bind to human complement component C9 to inhibit its polymerization, making the peptide a candidate therapeutic agent for complement-related immune disorders. Here, the peptide underwent an N-terminal modification with a membrane-targeting signal (a unique myristoylated peptide) to improve its therapeutic efficacy. We found that the modified peptide had a binding affinity to human C9 that was similar to that of the original peptide, as confirmed by microscale thermophoresis assays. The binding of the modified peptide to human C9 resulted in the inhibition of C9-related complement activation, as reflected by the decreased Zn-induced C9 polymerization and the decreased C9-dependent lysis of rabbit erythrocytes. In addition, the original and modified peptides could both bind to recombinant mouse C9 and inhibit the C9-dependent lysis of rabbit erythrocytes in normal mouse serum (NMS), which meant that the peptides could cross the species barrier to inhibit complement activity in mice. Further and analyses confirmed that the peptide modification increased the retention time of the peptide. Furthermore, intraarticular injection of the modified peptide markedly ameliorated knee swelling and joint damage in mice with antigen-induced arthritis (AIA), as assessed histologically. These results suggested that the -pmy-derived peptide modified with a membrane-targeting signal was a reasonable candidate therapeutic agent for membrane attack complex (MAC)-related diseases [such as rheumatoid arthritis (RA)] and the study presented a new modification method to improve the potential therapeutic effects of the peptide.
蠕虫来源的分子具有调节宿主免疫系统的能力。我们之前的研究鉴定出一种源自副肌球蛋白的十四肽（-pmy），它可以与人补体成分C9结合以抑制其聚合，使该肽成为补体相关免疫疾病的候选治疗剂。在此，该肽通过膜靶向信号（一种独特的肉豆蔻酰化肽）进行了N端修饰，以提高其治疗效果。我们发现，通过微量热泳分析证实，修饰后的肽与人C9的结合亲和力与原始肽相似。修饰后的肽与人C9的结合导致C9相关补体激活受到抑制，这表现为锌诱导的C9聚合减少以及兔红细胞C9依赖性裂解减少。此外，原始肽和修饰后的肽都可以与重组小鼠C9结合，并抑制正常小鼠血清（NMS）中兔红细胞的C9依赖性裂解，这意味着这些肽可以跨越物种屏障抑制小鼠体内的补体活性。进一步的分析证实，肽修饰增加了肽的保留时间。此外，组织学评估显示，关节内注射修饰后的肽可显著改善抗原诱导性关节炎（AIA）小鼠的膝关节肿胀和关节损伤。这些结果表明，用膜靶向信号修饰的-pmy衍生肽是膜攻击复合物（MAC）相关疾病[如类风湿性关节炎（RA）]的合理候选治疗剂，并且该研究提出了一种新的修饰方法来提高该肽的潜在治疗效果。
