大量研究表明，抗dsDNA抗体与系统性红斑狼疮（SLE）靶器官损害密切相关。因此，靶向阻断抗dsDNA IgG与自身抗原的结合是缓解组织损害的重要策略。我们最近发现，ALW多肽可明显减轻抗dsDNA抗体与自身抗原结合，减少MRL/lpr小鼠肾脏IgG沉积，但现有ALW多肽在体内易被酶切而失去活性。我们推测：对ALW进行化学修饰，可以提高其稳定性且不影响多肽功能，并采用纳米微粒制作缓释ALW多肽，有望高效靶向阻断抗dsDNA IgG体内的致病效应。本课题拟采用惰性氨基酸替换、糖基化等方法对ALW进行化学修饰，经体外分析其结构与功能变化，利用PLGA纳米微球构建缓释体系，在MRL/lpr小鼠体内进行组织器官定位示踪、生物降解等分析，最后观察治疗抗dsDNA IgG引起的靶器官病变的效果及副作用。本研究有助于开发高效稳定的多肽ALW药物（前体），为靶向阻断自身抗体导致的SLE器官损害奠定基础。

Many studies demonstrated that anti-dsDNA antibodies contribute to end-organ damage in patients with systemic lupus erythematosus (SLE). To block the binding of anti-dsDNA IgG to self-antigens is a promising strategy in the management of patients. Recently, we found that ALW peptide significantly decreased glomerular IgG deposition in MRL/lpr lupus-prone mice. Meanwhile，such peptide has low biological activity in vivo because of catalysis by anti-dsDNA antibodies. Thus, we speculated that chemical modifications may improve the stability of ALW peptide without affecting the antigenic structure and function. Moreover, polylactic-co-glycolic acid (PLGA)-ALW nanomicrospheres are expected to effectively target anti-dsDNA IgG. We plan to chemically modify ALW peptide using some approaches including inert amino acid substitution, glycosylation, etc., which may resist IgG catalysis. Also, the sustained release nanomicrospheres will be prepared by incorporation of ALW and PLGA. After in vitro evaluation of the structure and functions, such PLGA-ALW nanomicrospheres are to be intravenously injected into MRL/lpr mice. Then, the in vivo distribution and therapeutic/side effect of these nanomicrospheres will be analyzed systemically. The results from this study can help develop highly efficient and stable ALW peptide (prodrug), which is critical in the target therapies of autoantibody-related injuries in patients with SLE.