Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 12, Issue 11, Pages 1759-1765Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00374
Keywords
Influenza A virus; entry inhibitor; oleanolic acid; trimer; hemagglutinin
Categories
Funding
- National Natural Science Foundation of China (China) [22167018]
- Yunnan Fundamental Research Projects (China) [2019FB125]
- Open-Fund Program of the State Key Laboratory of Natural and Biomimetic Drugs (China) [K202003]
- Shenzhen Bay laboratory start up fund (China) [21230071]
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The designed and synthesized oleanolic acid (OA) trimers exhibited potent antiviral activities against influenza virus, potentially by interrupting the interaction between the virus and host cells to block viral entry. These findings suggest the utility of multivalent OA conjugates in enhancing ligand-target interactions for anti-influenza virus drug design.
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 12c, 12e, 13c, and 13d were observed to exhibit robust potency (IC50 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 (BAT). 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.
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