Electrophilic groups, such as Michael acceptors, expoxides, are common motifs in natural products (NPs). Electrophilic NPs can act through covalent modification of cysteinyl thiols on functional proteins, and exhibit potent cytotoxicity and anti-inflammatory/cancer activities. Here we describe a new chemoproteomic strategy, termed multiplexed thiol reactivity profiling (MTRP), and its use in target discovery of electrophilic NPs. We demonstrate the utility of MTRP by identifying cellular targets of gambogic acid, an electrophilic NP that is currently under evaluation in clinical trials as anticancer agent. Moreover, MTRP enables simultaneous comparison of seven structurally diversified α,β-unsaturated γ-lactones, which provides insights into the relative proteomic reactivity and target preference of diverse structural scaffolds coupled to a common electrophilic motif and reveals various potential druggable targets with liganded cysteines. We anticipate that this new method for thiol reactivity profiling in a multiplexed manner will find broad application in redox biology and drug discovery.

中文翻译：

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用于亲电子天然产物目标发现的多重巯基反应性分析

亲电基团（例如Michael受体，expoxides）是天然产物（NPs）中的常见基序。亲电纳米颗粒可以通过半胱氨酸巯基对功能蛋白的共价修饰来发挥作用，并表现出强大的细胞毒性和抗炎/抗癌活性。在这里，我们描述了一种新的化学计量学策略，称为多重硫醇反应谱（MTRP），及其在亲电NPs靶标发现中的用途。我们通过鉴定藤黄酸（一种亲电性NP，目前正在临床试验中评估其抗癌剂）的细胞靶标来证明MTRP的实用性。此外，MTRP可以同时比较7种结构多样的α，β-不饱和γ-内酯，它提供了洞察相对蛋白质组反应性和与共同的亲电子基序偶联的各种结构支架的靶标偏好，并揭示了配位半胱氨酸的各种潜在可药物靶标。我们预计，这种以多重方式进行硫醇反应性分析的新方法将在氧化还原生物学和药物发现中得到广泛应用。