Division of Pharmacognosy, Department of Medicinal Chemistry , Uppsala University , Biomedical Centre , Box 574, SE-75123 Uppsala , Sweden.
Rheumatology Unit, Department of Medicine-Solna , Karolinska Institutet, Karolinska University Hospital , Rheumatology Clinic D2:01 , 171 76 Solna, Stockholm , Sweden.
ACS Chem Biol. 2018 Jun 15;13(6):1525-1535. doi: 10.1021/acschembio.8b00118. Epub 2018 May 24.
The occurrence of autoantibodies is a hallmark of rheumatoid arthritis, specifically those autoantibodies targeting proteins containing the arginine-derived amino acid citrulline. There is strong evidence showing that the occurrence of anticitrullinated protein/peptide antibodies (ACPA) are involved in disease progression, and ACPA was recently shown to induce pain in animals. Here, we explore a novel concept useful for research, diagnostics, and possibly therapy of autoimmune diseases, namely, to directly target and neutralize autoantibodies using peptide binders. A high-affinity peptide-based scavenger of ACPA was developed by grafting a citrullinated epitope derived from human fibrinogen into a naturally occurring stable peptide scaffold. The best scavenger comprises the truncated epitope α-fibrinogen, [Cit573]fib(566-580), grafted into the scaffold sunflower trypsin inhibitor-1, SFTI-1. The final peptide demonstrates low nanomolar apparent affinity and superior stability.
自身抗体的出现是类风湿关节炎的一个标志，特别是针对含有精氨酸衍生氨基酸瓜氨酸的蛋白质的自身抗体。有强有力的证据表明，抗瓜氨酸化蛋白/肽抗体（ACPA）的出现与疾病进展有关，最近的研究表明 ACPA 可在动物中引起疼痛。在这里，我们探索了一个用于研究、诊断和可能治疗自身免疫性疾病的新概念，即用肽结合物直接靶向和中和自身抗体。通过将源自人纤维蛋白原的瓜氨酸化表位嫁接到天然存在的稳定肽支架上，开发出一种高亲和力的基于肽的 ACPA 清除剂。最佳的清除剂由截短的表位α-纤维蛋白原，[Cit573]fib（566-580），嫁接到支架万寿菊胰蛋白酶抑制剂-1，SFTI-1 中组成。最终的肽具有低纳摩尔的表观亲和力和优异的稳定性。
