Discovery of Pentacyclic Triterpenoid PROTACs as a Class of Effective Hemagglutinin Protein Degraders,Journal of Medicinal Chemistry

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Discovery of Pentacyclic Triterpenoid PROTACs as a Class of Effective Hemagglutinin Protein Degraders
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-17 , DOI: 10.1021/acs.jmedchem.1c02013
Haiwei Li ₁ , Shouxin Wang ₁ , Wenxiao Ma ₁ , Boyang Cheng ₁ , Yanliang Yi ₁ , Xinyuan Ma ₁ , Sulong Xiao ₁ , Lihe Zhang ₁ , Demin Zhou _{1,

2,

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Affiliation

Influenza hemagglutinin that drives viral entry into cells via the membrane fusion process is an up-and-coming antiviral drug target. Herein, we described for the first time the design, synthesis, and biological characteristics of a new class of pentacyclic triterpenoid-based proteolysis targeting chimeras (PROTACs) to enhance the degradation of hemagglutinin target. Among these PROTACs, V3 showed the best degradation effect on the hemagglutinin with a median degradation concentration of 1.44 μM in a ubiquitin and proteasome-dependent manner and broad-spectrum anti-influenza A virus activity but not affected the entry of influenza virus. Moreover, intravenous injection of V3 protected mice against influenza A virus-induced toxic effects. Further diazirine-containing photo-crosslinking mass spectrometric analysis of hemagglutinin complexes indicated crosslinking to Asn15, Thr31, and Asn27, a novel target of hemagglutinin. Taken together, our data revealed that oleanolic acid-based PROTACs could degrade hemagglutinin protein, providing a new direction toward the discovery of potential anti-influenza drugs.

中文翻译：

发现五环三萜类 PROTACs 作为一类有效的血凝素蛋白降解剂

通过膜融合过程驱动病毒进入细胞的流感血凝素是一种新兴的抗病毒药物靶点。在此，我们首次描述了一类新型五环三萜类蛋白水解靶向嵌合体（PROTACs）的设计、合成和生物学特性，以增强血凝素靶标的降解。在这些PROTAC中，V3对血凝素的降解效果最好，中位降解浓度为1.44 μM，呈泛素和蛋白酶体依赖性，具有广谱抗甲型流感病毒活性，但不影响流感病毒的进入。此外，静脉注射V3保护小鼠免受甲型流感病毒引起的毒性作用。进一步对血凝素复合物进行含二氮丙啶的光交联质谱分析表明与血凝素的新靶标 Asn15、Thr31 和 Asn27 交联。综上所述，我们的数据显示，基于齐墩果酸的 PROTAC 可以降解血凝素蛋白，为发现潜在的抗流感药物提供了新的方向。

更新日期：2022-05-17

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