Ricklin Daniel, Lambris John D
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Adv Exp Med Biol. 2008;632:273-92. doi: 10.1007/978-0-387-78952-1_20.
Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic.
对人类补体系统进行治疗性调节被认为是治疗多种病理状况的一种有前景的方法。由于其在补体级联反应中的核心地位，补体成分C3是补体特异性药物特别有吸引力的靶点。Compstatin是一种环状十三肽，最初从噬菌体展示文库中发现，是一种高效且选择性的C3抑制剂，在一系列实验模型中显示出临床潜力。化学、生物物理和计算方法的结合显著优化了其对C3的结合亲和力及其抑制效力。随着最近宣布用一种compstatin类似物进行治疗年龄相关性黄斑变性的临床试验，在其成为药物的道路上又达到了一个重要的里程碑。此外，compstatin与C3c的共晶体结构的公布使得能够详细了解其结合模式，并为合理设计具有更高活性的肽和模拟物铺平了道路。考虑到新的激励因素和有前景的临床前结果，compstatin似乎为其成为临床治疗药物道路上的挑战做好了充分准备。
