Integrated Thermal Proteome Profiling and Affinity Ultrafiltration Mass Spectrometry (iTPAUMS): A Novel Paradigm for Elucidating the Mechanism of Action of Natural Products,Analytical Chemistry

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Integrated Thermal Proteome Profiling and Affinity Ultrafiltration Mass Spectrometry (iTPAUMS): A Novel Paradigm for Elucidating the Mechanism of Action of Natural Products
Analytical Chemistry ( IF 6.7 ) Pub Date : 2024-09-10 , DOI: 10.1021/acs.analchem.4c03398
Hengyuan Yu ₁ , Yang Chen ₂ , Yichen Wang ₁ , Weiliang Fu ₁ , Rui Xu ₁ , Jie Liu _{1,

3,

4} , Yong Chen _{1,

5} , Xuesong Liu _{1,

5} , Yongjiang Wu ₁ , Tengfei Xu _{1,

5}

Affiliation

Natural products (NPs) are foundational to drug discovery, offering a rich repertoire of molecular diversity with multifaceted modes of action against a broad array of targets. Despite their potential, deconvoluting the intricate mechanism of action (MoA) of NPs, characterized by their multicomponent, multitarget, and multilevel interactions, remains a formidable challenge. Here, we introduce an innovative pipeline called integrated thermal proteome profiling and affinity ultrafiltration mass spectrometry (iTPAUMS). This approach combines the high-throughput capacity of thermal proteome profiling (TPP) with the specificity of affinity ultrafiltration mass spectrometry (AUMS), creating a powerful toolkit for elucidating complex MoAs of NPs. Significantly, our investigation represents a pioneering application of TPP to delineate the target group of NPs mixtures and overcome the long-standing obstacle of mapping specific component-target interactions through AUMS. Our findings demonstrate the utility of iTPAUMS in constructing a comprehensive component-target atlas, providing a robust analytical foundation for unraveling the intricate pharmacological landscapes of NPs and advancing drug discovery.

中文翻译：

集成热蛋白质组分析和亲和超滤质谱（iTPAUMS）：阐明天然产物作用机制的新范式

天然产物（NP）是药物发现的基础，具有丰富的分子多样性，具有针对广泛靶标的多方面作用模式。尽管它们具有潜力，但解开 NP 错综复杂的作用机制（MoA）仍然是一项艰巨的挑战，其特征是其多组分、多靶点和多水平相互作用。在这里，我们介绍了一种称为集成热蛋白质组分析和亲和超滤质谱（iTPAUMS）的创新管道。这种方法将热蛋白质组分析（TPP）的高通量容量与亲和超滤质谱（AUMS）的特异性相结合，为阐明 NP 的复杂 MoA 创建了一个强大的工具包。值得注意的是，我们的研究代表了 TPP 的开创性应用，用于描述 NPs 混合物的目标组，并克服了通过 AUMS 映射特定组分-目标相互作用的长期障碍。我们的研究结果表明 iTPAUMS 在构建全面的组分靶点图谱方面的效用，为解开 NP 错综复杂的药理学景观和推进药物发现提供了强大的分析基础。

更新日期：2024-09-10

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