Department of Chemistry, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden.
J Med Chem. 2012 Mar 22;55(6):2549-60. doi: 10.1021/jm201517a. Epub 2012 Mar 14.
A series of eight peptides corresponding to the amino acid sequence of the hinge region of IgG and 17 newly synthesized peptide analogues containing a piperidine moiety as a replacement of a glycine residue were tested as potential inhibitors of the bacterial IgG degrading enzyme of Streptococcus pyogenes , IdeS. None of the peptides showed any inhibitory activity of IdeS, but several piperidine-based analogues were identified as inhibitors. Two different analysis methods were used: an SDS-PAGE based assay to detect IgG cleavage products and a surface plasmon resonance spectroscopy based assay to quantify the degree of inhibition. To investigate the selectivity of the inhibitors for IdeS, all compounds were screened against two other related cysteine proteases (SpeB and papain). The selectivity results show that larger analogues that are active inhibitors of IdeS are even more potent as inhibitors of papain, whereas smaller analogues that are active inhibitors of IdeS inhibit neither SpeB nor papain. Two compounds were identified that exhibit high selectivity against IdeS and will be used for further studies.
一系列对应 IgG 铰链区氨基酸序列的 8 个肽和 17 个新合成的含有哌啶部分代替甘氨酸残基的肽类似物被测试为潜在的抑制物链球菌的 IgG 降解酶，IdeS。没有一个肽显示出 IdeS 的任何抑制活性，但鉴定出了几种基于哌啶的类似物作为抑制剂。使用了两种不同的分析方法：基于 SDS-PAGE 的测定法来检测 IgG 切割产物和基于表面等离子体共振光谱学的测定法来定量抑制程度。为了研究抑制剂对 IdeS 的选择性，所有化合物都针对另外两种相关的半胱氨酸蛋白酶（SpeB 和木瓜蛋白酶）进行了筛选。选择性结果表明，作为 IdeS 的有效抑制剂的较大类似物，作为木瓜蛋白酶的抑制剂的活性甚至更高，而作为 IdeS 的有效抑制剂的较小类似物既不抑制 SpeB 也不抑制木瓜蛋白酶。已经鉴定出两种对 IdeS 表现出高选择性的化合物，将用于进一步研究。
