靶向 SOCS1 的 SH2 结构域并阻断底物泛素化的磷酸酪氨酸肽的优化,ACS Chemical Biology

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靶向 SOCS1 的 SH2 结构域并阻断底物泛素化的磷酸酪氨酸肽的优化
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2022-01-06 , DOI: 10.1021/acschembio.1c00884
Hao Chen _{1,

2} , Yuntong Wu _{1,

2} , Kunlun Li _{1,

2} , Iain Currie _{1,

2} , Narelle Keating _{1,

2} , Farhad Dehkhoda _{1,

2} , Christoph Grohmann _{1,

2} , Jeffrey J Babon _{1,

2} , Sandra E Nicholson _{1,

2} , Brad E Sleebs _{1,

2}

Affiliation

细胞因子信号通路抑制剂 1 (SOCS1) 已成为炎症和病毒性疾病的潜在治疗靶点。SOCS1 通过其激酶抑制区域、Src 同源 2 (SH2) 结构域和 SOCS 盒来负调控 Janus 激酶/信号转导和转录信号通路的激活剂。在本研究中，我们利用天然磷酸酪氨酸肽底物作为起点，反复探索每个氨基酸位置靶向 SOCS1 的 SH2 结构域的要求。我们表明，肽底物中各自的 -1、+1、+2、+3 和 +5 位置的 Met、Thr、Thr、Val 和 Asp 有利于与 SOCS1-SH2 结构域结合并识别几种磷酸酪氨酸与 IC ₅₀具有强 SOCS1 结合亲和力的肽值范围为 20 至 70 nM，对密切相关的 SOCS 家族蛋白 CIS、SOCS2 和 SOCS3 的选择性超过 100 倍。优化的磷酸酪氨酸肽在使用细胞裂解物的热迁移分析中显示稳定 SOCS1，并在生化分析中抑制 SOCS1 介导的靶底物泛素化。总的来说，这些数据提供了开发细胞渗透性肽模拟物的框架，进一步研究 SOCS1-SH2 结构域作为炎症和病毒性疾病治疗靶点的潜力。

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Optimization of Phosphotyrosine Peptides that Target the SH2 Domain of SOCS1 and Block Substrate Ubiquitination

Suppressor of cytokine signaling 1 (SOCS1) has emerged as a potential therapeutic target in inflammatory and viral diseases. SOCS1 operates via its kinase inhibitory region, Src homology 2 (SH2) domain, and SOCS box to negatively regulate the Janus kinase/signal transducers and activators of transcription signaling pathway. In this study, we utilized native phosphotyrosine peptide substrates as a starting point to iteratively explore the requirement of each amino acid position to target the SH2 domain of SOCS1. We show that Met, Thr, Thr, Val, and Asp in the respective −1, +1, +2, +3, and +5 positions within the peptide substrate are favored for binding to the SOCS1-SH2 domain and identifying several phosphotyrosine peptides that have potent SOCS1 binding affinity with IC₅₀ values ranging from 20 to 70 nM and greater than 100-fold selectivity against the closely related SOCS family proteins, CIS, SOCS2, and SOCS3. The optimized phosphotyrosine peptide was shown to stabilize SOCS1 in a thermal shift assay using cell lysates and inhibited SOCS1-mediated ubiquitination of a target substrate in a biochemical assay. Collectively, these data provide the framework to develop cell-permeable peptidomimetics that further investigate the potential of the SOCS1-SH2 domain as a therapeutic target in inflammatory and viral diseases.

更新日期：2022-01-06

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