用于邻近诱导半胱氨酸交联的化学选择性 Cys-Pen 二硫化物,ACS Chemical Biology

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用于邻近诱导半胱氨酸交联的化学选择性 Cys-Pen 二硫化物
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2022-02-28 , DOI: 10.1021/acschembio.2c00083
Mei-Miao Zhan ₁ , Rui Wang ₂ , Zhihong Liu ₁ , Na Liu ₁ , Yuxin Ye ₂ , Mingchan Liang ₂ , Yichi Zhang ₁ , Chenran Jiang ₂ , Feng Yin ₂ , Zigang Li _{1,

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Affiliation

富含二硫化物的结构是有价值的药理学工具或治疗剂。此外，配体诱导的偶联策略在新型共价药物的效力、选择性和作用持续时间方面具有潜在优势。通过硫醇-二硫键交换将丰富的富含二硫键的结构库和配体诱导的偶联物结合起来，将为开发位点特异性共价抑制剂提供巨大的好处。半胱氨酸-半胱氨酸（Cys-Cys）二硫键在内源性还原环境中本质上是不稳定的，而半胱氨酸-青霉胺（Cys-Pen）二硫键表现出令人满意的稳定性。我们设想 Cys-Pen 二硫化物是一种潜在的配体诱导的共价键合弹头，这种二硫化物可以与肽结合位点附近的蛋白质半胱氨酸重建形成新的二硫化物。为了评估我们的设计，蛋白质 PLCγ1-c src 同源性 2 域和 RGS3-PDZ 域作为模型进行了测试。两种蛋白质都被 Cys-Pen 二硫化物成功修饰，并在蛋白质和肽之间形成了新的二硫化物。然后分析新的二硫键以确认它是配体的Pen与配体结合位点附近的蛋白质Cys之间新形成的二硫键。然后通过利用其催化袋附近的“CXXC”域选择 HDAC4 作为模型。设计的HDAC4 Cys-Pen环肽抑制剂表现出令人满意的选择性和抑制作用。然后分析新的二硫键以确认它是配体的Pen与配体结合位点附近的蛋白质Cys之间新形成的二硫键。然后通过利用其催化袋附近的“CXXC”域选择 HDAC4 作为模型。设计的HDAC4 Cys-Pen环肽抑制剂表现出令人满意的选择性和抑制作用。然后分析新的二硫键以确认它是配体的Pen与配体结合位点附近的蛋白质Cys之间新形成的二硫键。然后通过利用其催化袋附近的“CXXC”域选择 HDAC4 作为模型。设计的HDAC4 Cys-Pen环肽抑制剂表现出令人满意的选择性和抑制作用。

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Chemo-Selective Cys–Pen Disulfide for Proximity-Induced Cysteine Cross-Linking

Disulfide-rich architectures are valuable pharmacological tools or therapeutics. Besides, a ligand-induced conjugate strategy offers potential advantages in potency, selectivity, and duration of action for novel covalent drugs. Combining the plentiful disulfide-rich architecture library and ligand-induced conjugate via thiol–disulfide interchange would supply great benefits for developing site specific covalent inhibitors. Cysteine–cysteine (Cys–Cys) disulfide bonds are intrinsically unstable in endogenous reductive environment, while cysteine–penicillamine (Cys–Pen) disulfide bonds show satisfactory stability. We envisioned the Cys–Pen disulfide as a potential ligand-induced covalent bonding warhead, and this disulfide could reconstruct with the protein cysteine in the vicinity of the peptide binding site to form a new disulfide. To evaluate our design, protein PLCγ1-c src homology 2 domain and RGS3-PDZ domain were tested as models. Both proteins were successfully modified by Cys–Pen disulfide and formed new disulfides between proteins and peptides. The new disulfide was then analyzed to confirm it was a newly formed disulfide bond between Pen of the ligand and a protein Cys near the ligand binding site. HDAC4 was then chosen as a model by utilizing its “CXXC” domain near its catalytic pocket. The designed Cys–Pen cyclic peptide inhibitor of HDAC4 showed satisfactory selectivity and inhibitory effect.

更新日期：2022-02-28

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