Macrocyclic peptides that inhibit Wnt signalling via interaction with Wnt3a,RSC Chemical Biology

当前位置： X-MOL 学术 › RSC Chem. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Macrocyclic peptides that inhibit Wnt signalling via interaction with Wnt3a
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-03-24 , DOI: 10.1039/d0cb00016g
Manuel E Otero-Ramirez ₁ , Kyoko Matoba ₂ , Emiko Mihara ₂ , Toby Passioura _{1,

3} , Junichi Takagi ₂ , Hiroaki Suga ₁

Affiliation

Here we report de novo macrocyclic peptide binders to Wnt3a, a member of the Wnt protein family. By means of the Random non-standard Peptides Integrated Discovery (RaPID) system, we have performed in vitro selection against the complex of mouse Wnt3a (mWnt3a) with human afamin (hAFM) to discover macrocyclic peptides that bind mWnt3a with K_D values as tight as 110 nM. One of these peptides, WAp-D04 (Wnt–AFM-peptide-D04), was able to inhibit the receptor-mediated signaling process, which was demonstrated in a Wnt3a-dependent reporter cell-line. Based on this initial hit, we applied a block-mutagenesis scanning display to identify a mutant inhibitor, WAp-D04-W10P, with 5-fold greater potency in a reporter assay. This work represents the first instance of molecules capable of inhibiting Wnt signaling through direct interaction with a Wnt protein, a molecular class for which targeting has been challenging due its highly hydrophobic nature.

中文翻译：

通过与 Wnt3a 相互作用抑制 Wnt 信号传导的大环肽

在这里，我们向 Wnt3a（Wnt 蛋白家族的成员）报告了从头大环肽结合剂。通过随机非标准肽综合发现 (RaPID) 系统，我们对小鼠 Wnt3a (mWnt3a) 与人 afamin (hAFM) 的复合物进行了体外选择，以发现将 mWnt3a 与K _D结合的大环肽值紧至 110 nM。其中一种肽 WAp-D04（Wnt-AFM-肽-D04）能够抑制受体介导的信号传导过程，这在 Wnt3a 依赖性报告细胞系中得到证实。基于这一初始命中，我们应用了块诱变扫描显示来鉴定突变抑制剂 WAp-D04-W10P，其在报告基因检测中的效力提高了 5 倍。这项工作代表了能够通过与 Wnt 蛋白直接相互作用抑制 Wnt 信号传导的分子的第一个实例，Wnt 蛋白是一种分子类别，由于其高度疏水性，其靶向一直具有挑战性。

更新日期：2020-03-24

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文