Gorham Ronald D, Forest David L, Khoury George A, Smadbeck James, Beecher Consuelo N, Healy Evangeline D, Tamamis Phanourios, Archontis Georgios, Larive Cynthia K, Floudas Christodoulos A, Radeke Monte J, Johnson Lincoln V, Morikis Dimitrios
Department of Bioengineering, University of California , Riverside, California 92521, United States.
J Med Chem. 2015 Jan 22;58(2):814-26. doi: 10.1021/jm501345y. Epub 2014 Dec 29.
Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, cyclized between C2 and C12), based on structural, computational, and experimental studies. Furthermore, we developed and utilized a computational framework for the design of peptides containing non-natural amino acids. These new compstatin peptides contain polar N-terminal extensions and non-natural amino acid substitutions at positions 4 and 9. Peptides with α-modified non-natural alanine analogs at position 9, as well as peptides containing only N-terminal polar extensions, exhibited similar activity compared to W4A9, as quantified via ELISA, hemolytic, and cell-based assays, and showed improved solubility, as measured by UV absorbance and reverse-phase HPLC experiments. Because of their potency and solubility, these peptides are promising candidates for therapeutic development in numerous complement-mediated diseases.
补体抑制素肽是一类补体抑制剂，可结合并抑制补体C3的裂解。肽的结合通过疏水相互作用得以增强；然而，溶解性差会促使其在水性环境中聚集。基于结构、计算和实验研究，我们设计了源自W4A9序列（Ac-ICVWQDWGAHRCT-NH2，在C2和C12之间环化）的新型补体抑制素肽。此外，我们开发并利用了一个计算框架来设计含有非天然氨基酸的肽。这些新型补体抑制素肽在第4和9位含有极性N端延伸以及非天然氨基酸取代。通过ELISA、溶血和基于细胞的检测方法定量分析，第9位带有α修饰的非天然丙氨酸类似物的肽，以及仅含有N端极性延伸的肽，与W4A9表现出相似的活性，并且通过紫外吸收和反相高效液相色谱实验测定，它们的溶解性有所改善。由于其效力和溶解性，这些肽有望成为众多补体介导疾病治疗开发的候选药物。
