Shao Liang, Yang Fan, Su Yangqing, Li Weijia, Zhang Jihong, Xu Huan, Huang Boxuan, Sun Mengsi, Mu Yu, Zhang Yuan, Yu Fei
Medical School of Kunming University of Science and Technology, Kunming, Yunnan 650500, China.
Institute of Chemical Biology, Shenzhen Bay Laboratories, Shenzhen, Guangdong 518132, China.
ACS Med Chem Lett. 2021 Nov 2;12(11):1759-1765. doi: 10.1021/acsmedchemlett.1c00374. eCollection 2021 Nov 11.
Influenza is a major threat to millions of people worldwide. Entry inhibitors are of particular interest for the development of novel therapeutic strategies for influenza. We have previously discovered oleanolic acid (OA) to be a mild influenza hemagglutinin (HA) inhibitor. In this work, inspired by the 3D structure of HA as a homotrimeric receptor, we designed and synthesized 15 OA trimers with different linkers and central region via the copper-catalyzed azide-alkyne cycloaddition reaction. All of the OA trimers were evaluated for their antiviral activities in vitro, and , , , and were observed to exhibit robust potency (IC in the submicromolar range) against influenza A/WSN/33 (H1N1) virus that was stronger than that observed with oseltamivir. In addition, these compounds also displayed strong biological activity against A/Hong Kong/4801/2014 and B/Sichuan/531/2018 (BV). The results of hemagglutination inhibition assays and surface plasmon resonance binding assays suggest that these OA trimers may interrupt the interaction between the HA protein of influenza virus and the host cell sialic acid receptor, thus blocking viral entry. These findings highlight the utility of multivalent OA conjugates to enhance the ligand-target interactions in anti-influenza virus drug design and are also helpful for studying antiviral drugs derived from natural products.
流感是全球数百万人面临的重大威胁。进入抑制剂对于开发新型流感治疗策略尤为重要。我们之前发现齐墩果酸（OA）是一种温和的流感血凝素（HA）抑制剂。在这项工作中，受HA作为同源三聚体受体的三维结构启发，我们通过铜催化的叠氮化物-炔烃环加成反应设计并合成了15种带有不同连接基和中心区域的OA三聚体。对所有OA三聚体进行了体外抗病毒活性评估，发现[具体化合物名称1]、[具体化合物名称2]、[具体化合物名称3]和[具体化合物名称4]对甲型流感病毒A/WSN/33（H1N1）表现出强大的效力（IC处于亚微摩尔范围），比奥司他韦更强。此外，这些化合物对A/香港/4801/2014和B/四川/531/2018（BV）也显示出强大的生物活性。血凝抑制试验和表面等离子体共振结合试验结果表明，这些OA三聚体可能会中断流感病毒的HA蛋白与宿主细胞唾液酸受体之间的相互作用，从而阻断病毒进入。这些发现突出了多价OA缀合物在增强抗流感病毒药物设计中配体-靶点相互作用方面的效用，也有助于研究天然产物衍生的抗病毒药物。
