Inhibition of the EphA2-Sam/Ship2-Sam Association through Peptide Ligands: Studying the Combined Effect of Charge and Aromatic Character,Journal of Medicinal Chemistry

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Inhibition of the EphA2-Sam/Ship2-Sam Association through Peptide Ligands: Studying the Combined Effect of Charge and Aromatic Character
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-11 , DOI: 10.1021/acs.jmedchem.4c01459
Marian Vincenzi ₁ , Flavia A Mercurio ₁ , Rosanna Palumbo ₁ , Sara La Manna ₂ , Luciano Pirone ₁ , Daniela Marasco _{1,

2} , Emilia M Pedone ₁ , Marilisa Leone ₁

Affiliation

The Sam (sterile alpha motif) domain from the lipid phosphatase Ship2 binds the Sam domain from the EphA2 receptor to negatively regulate receptor endocytosis and degradation. This interaction is primarily linked to pro-oncogenic effects. We report on the design and evaluation of EphA2-Sam/Ship2-Sam peptide inhibitors provided with positive charges and different aromatic characters. Starting from the sequence of previously identified Ship2-Sam targeting peptides, an in silico approach was set up to predict higher affinity peptide ligands. A few peptides were experimentally tested through an interdisciplinary approach. Interaction studies were performed by nuclear magnetic resonance spectroscopy and biolayer interferometry. 3D models of Ship2-Sam/peptide complexes were predicted by AlphaFold2. Cell-based assays were carried out to investigate whether such peptide sequences might have an influence on EphA2 signaling. The approach led to the identification of novel Ship2-Sam ligands and shed further light on original approaches to design inhibitors of the Ship2-Sam/EphA2-Sam interaction.

中文翻译：

通过肽配体抑制 EphA2-Sam/Ship2-Sam 缔合：研究电荷和芳香特征的综合效应

脂质磷酸酶 Ship2 的 Sam（无菌 α 基序）结构域与 EphA2 受体的 Sam 结构域结合，负向调节受体的内吞作用和降解。这种相互作用主要与促癌作用有关。我们报告了带有正电荷和不同芳香特征的 EphA2-Sam/Ship2-Sam 肽抑制剂的设计和评估。从先前鉴定的 Ship2-Sam 靶向肽的序列开始，建立了一种计算机方法来预测更高亲和力的肽配体。通过跨学科方法对一些肽进行了实验测试。通过核磁共振波谱和生物层干涉测量法进行相互作用研究。 Ship2-Sam/肽复合物的 3D 模型由 AlphaFold2 预测。我们进行了基于细胞的测定，以研究此类肽序列是否可能对 EphA2 信号传导产生影响。该方法导致了新型 Ship2-Sam 配体的鉴定，并进一步阐明了设计 Ship2-Sam/EphA2-Sam 相互作用抑制剂的原始方法。

更新日期：2024-09-11

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