Inhibition of the Ubiquitin Transfer Cascade by a Peptidomimetic Foldamer Mimicking the E2 N-Terminal Helix
Inhibition of the Ubiquitin Transfer Cascade by a Peptidomimetic Foldamer Mimicking the E2 N-Terminal Helix
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DOI：
10.1021/acs.jmedchem.2c01459
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发表时间：
2022-12-26
影响因子：
7.3
通讯作者：
Huang，Bo
中科院分区：
文献类型：
--
作者：
Zhou，Li;Jeong，In Ho;Huang，Bo
泛素转移的酶级联调节关键的细胞过程，是治疗癌症和神经退行性疾病的药物开发的焦点。E1位于UB传递级联的顶端，抑制E1的分子已显示出抑制癌细胞增殖的良好活性。与小分子相比，拟肽物已成为破坏蛋白质-蛋白质相互作用（PPI）的强大工具，在细胞中具有较小的耐药性和高稳定性。在此，我们利用d -磺酰γ- aa肽模拟E2的n端螺旋，从而抑制E1-E2相互作用。通过体外和细胞实验，两种钉接肽模拟物m1 - s1和m1 - s2被鉴定为阻断UB从E1到E2转移的有效抑制剂。我们的工作表明，在E1-E2和E2 - e3界面上具有E2 n端螺旋的PPIs可能是设计细胞中蛋白质泛素化途径抑制剂的一个有希望的靶点。
The enzymatic cascades for ubiquitin transfer regulate key cellular processes and are the intense focus of drug development for treating cancer and neurodegenerative diseases. E1 is at the apex of the UB transfer cascade, and molecules inhibiting E1 have shown promising activities against cancer cell proliferation. Compared to small molecules, peptidomimetics have emerged as powerful tools to disrupt the protein–protein interactions (PPI) with less drug resistance and high stability in the cell. Herein, we harnessed the D-sulfono-γ-AA peptide to mimic the N-terminal helix of E2 and thereby inhibit E1–E2 interaction. Two stapled peptidomimetics,M1–S1andM1–S2, were identified as effective inhibitors to block UB transfer from E1 to E2, as shown byin vitroand cellular assays. Our work suggested that PPIs with the N-terminal helix of E2 at the E1–E2 and E2–E3 interfaces could be a promising target for designing inhibitors against protein ubiquitination pathways in the cell.