Zhang Lin, Shen Hao, Gong Yiyi, Pang Xiaojing, Yi Meiqi, Guo Lin, Li Jin, Arroyo Sam, Lu Xin, Ovchinnikov Sergey, Cheng Gong, Liu Xudong, Jiang Xu, Feng Shan, Deng Haiteng
MOE Key Laboratory of Bioinformatics , Center for Synthetic and Systems Biology , School of Life Sciences , Tsinghua University , Beijing , China . Email:
Institute for Protein Design , Department of Biochemistry , University of Washington , Seattle , WA , USA.
Chem Sci. 2019 Jan 28;10(11):3271-3280. doi: 10.1039/c8sc05273e. eCollection 2019 Mar 21.
Targeted antibody blocking enables characterization of binding sites on immunoglobulin G (IgG), and can efficiently eliminate harmful antibodies from organisms. In this report, we present a novel peptide-denoted as a dual-functional conjugate of antigenic peptide and Fc-III mimetics (DCAF)-for targeted blocking of antibodies. Synthesis of DCAF was achieved by native chemical ligation, and the molecule consists of three functional parts: a specific antigenic peptide, a linker and the Fc-III mimetic peptide, which has a high affinity toward the Fc region of IgG molecules. We demonstrate that DCAF binds the cognate antibody with high selectivity by simultaneously binding to the Fab and Fc regions of IgG. Animal experiments revealed that DCAF molecules diminish the antibody-dependent enhancement effect in a dengue virus infection model, and rescue the acetylcholine receptor by inhibiting the complement cascade in a model. These results suggest that DCAFs could have utility in the development of new therapeutics against harmful antibodies.
靶向抗体阻断能够对免疫球蛋白G（IgG）上的结合位点进行表征，并能有效清除生物体中的有害抗体。在本报告中，我们提出了一种新型肽——抗原肽与Fc-III模拟物的双功能缀合物（DCAF）——用于靶向阻断抗体。DCAF的合成通过天然化学连接实现，该分子由三个功能部分组成：一个特异性抗原肽、一个连接子和Fc-III模拟肽，后者对IgG分子的Fc区域具有高亲和力。我们证明，DCAF通过同时结合IgG的Fab和Fc区域，以高选择性结合同源抗体。动物实验表明，DCAF分子在登革病毒感染模型中减弱了抗体依赖性增强效应，并在一个模型中通过抑制补体级联反应来挽救乙酰胆碱受体。这些结果表明，DCAF在开发针对有害抗体的新疗法中可能具有实用性。
