约束性环肽作为CD2：CD58蛋白与蛋白质相互作用的免疫调节抑制剂。,ACS Chemical Biology

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约束性环肽作为CD2：CD58蛋白与蛋白质相互作用的免疫调节抑制剂。
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2016-07-01 00:00:00 , DOI: 10.1021/acschembio.6b00486
Rushikesh Sable ₁ , Thomas Durek ₂ , Veena Taneja ₃ , David J. Craik ₂ , Sandeep Pallerla ₁ , Ted Gauthier ₄ , Seetharama Jois ₁

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细胞间粘附蛋白CD2和CD58之间的相互作用在淋巴细胞募集到炎症部位中起着至关重要的作用，这种相互作用的抑制剂作为自身免疫性疾病中的免疫调节药物具有潜力。来自CD2粘附域的肽被设计为抑制CD2：CD58相互作用。为了提高肽的稳定性，将涉及CD58识别的CD2区的β-折叠表位嫁接到向日葵胰蛋白酶抑制剂和恒河猴防御素的环状肽构架中。在三种不同的细胞粘附试验中评估了设计的多环肽调节细胞间相互作用的能力，其中一种候选药物为SFTI-a，显示出在纳摩尔范围内的有效活性（IC ₅₀：51 nM）。该肽还抑制了得自患有自身免疫性疾病类风湿关节炎的小鼠的T细胞中的免疫反应。SFTI-a对热变性具有抗性，这是通过圆二色性光谱法和质谱法判断的，在人血清中的半衰期约为24小时。通过分子对接研究预测该肽与CD58的结合，并通过表面等离振子共振实验通过实验证实。我们的结果表明，天然来源的环状肽是有希望的支架，可调节通常很难用小分子化合物靶向的蛋白质间相互作用。

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Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein–Protein Interaction

The interaction between the cell–cell adhesion proteins CD2 and CD58 plays a crucial role in lymphocyte recruitment to inflammatory sites, and inhibitors of this interaction have potential as immunomodulatory drugs in autoimmune diseases. Peptides from the CD2 adhesion domain were designed to inhibit CD2:CD58 interactions. To improve the stability of the peptides, β-sheet epitopes from the CD2 region implicated in CD58 recognition were grafted into the cyclic peptide frameworks of sunflower trypsin inhibitor and rhesus theta defensin. The designed multicyclic peptides were evaluated for their ability to modulate cell–cell interactions in three different cell adhesion assays, with one candidate, SFTI-a, showing potent activity in the nanomolar range (IC₅₀: 51 nM). This peptide also suppresses the immune responses in T cells obtained from mice that exhibit the autoimmune disease rheumatoid arthritis. SFTI-a was resistant to thermal denaturation, as judged by circular dichroism spectroscopy and mass spectrometry, and had a half-life of ∼24 h in human serum. Binding of this peptide to CD58 was predicted by molecular docking studies and experimentally confirmed by surface plasmon resonance experiments. Our results suggest that cyclic peptides from natural sources are promising scaffolds for modulating protein–protein interactions that are typically difficult to target with small-molecule compounds.

更新日期：2016-07-01

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