Nine-valent oleanolic acid conjugates as potent inhibitors blocking the entry of influenza A virus.

The influenza pandemic remains a major public health challenge that endangers the lives of many vulnerable and immune-compromised individuals worldwide. The high infectivity and genetic variability of influenza virus make it particularly challenging to design effective drugs to inhibit the virus. In previous studies, we determined that oleanolic acid (OA) and its derivatives block interactions between influenza and host cells, thus endowing OA with anti-viral efficacy. Inspired by the role of cluster glycosides in the interactions between hemagglutinins (HA) and sialic acid receptors (SA), we designed and synthesized a series of OA nonamers via the CuAAC reaction, and evaluated their anti-viral activities in vitro. We determined that among these nonamers, compound 15 displayed the highest potency (IC 50 = 5.23 μM), equivalent to the antiviral drug oseltamivir which is routinely prescribed for influenza A virus strain A/WSN/33 (H1N1). In addition, these compounds also displayed antiviral activity against influenza B. Mechanistic experiments indicated that OA nonamers can effectively target the influenza HA protein. This study collectively demonstrates that multivalent structure-activity binding strategy is an effective method for designing influenza virus inhibitors. OA nonamers can inhibit the entry of influenza virus by targeting the HA protein more effectively than OA monomers. [Display omitted] • A series of OA nonamers were designed and synthesized via the CuAAC reaction and their anti-influenza virus activities were evaluated. • The SAR of these OA nonamers as influenza virus inhibitors was summarized. • Among these OA nonamers, 15 and 16 displayed the highest anti-influenza A/WSN/33 activity. • The mechanism study suggested that OA nonamers 15 and 16 might bind to HA protein. [ABSTRACT FROM AUTHOR]