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 (IC50 = 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.

Design and Synthesis of Oleanolic Acid Trimers to Enhance Inhibition of Influenza Virus Entry.

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 (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.

Design, synthesis and biological evaluation of amino acids-oleanolic acid conjugates as influenza virus inhibitors.

Viral entry inhibitors are of great importance in current efforts to develop a new generation of anti-influenza drugs. Inspired by the discovery of a series of pentacyclic triterpene derivatives as entry inhibitors targeting the HA protein of influenza virus, we designed and synthesized 32 oleanolic acid (OA) analogues in this study by conjugating different amino acids to the 28-COOH of OA. The antiviral activity of these compounds was evaluated in vitro. Some of these compounds revealed impressive anti-influenza potencies against influenza A/WSN/33 (H1N1) virus. Among them, compound 15a exhibited robust potency and broad antiviral spectrum with IC50 values at the low-micromolar level against four different influenza strains. Hemagglutination inhibition (HI) assay and docking experiment indicated that these OA analogues may act in the same way as their parent compound by interrupting the interaction between HA protein of influenza virus and the host cell sialic acid receptor via binding to HA, thus blocking viral entry.

Synthesis, Structure Activity Relationship and Anti-influenza A Virus Evaluation of Oleanolic Acid-Linear Amino Derivatives.

Oleanolic acid (OA) was discovered as a mild influenza hemagglutinin (HA) inhibitor in our earlier studies. In the present work, 20 compounds were prepared by structural modifications of OA, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in Madin-Darby canine kidney (MDCK) cells were evaluated. Based on the biological result, structure-activity relationship (SAR) was discussed. Compound 10 with six-carbon chain and a terminal hydroxyl group showed the strongest anti-influenza activity with an IC50 of 2.98 µM, which is an order of magnitude more potent than OA. Hemagglutination inhibition and Surface plasmon resonance (SPR) assay indicated that compound 10 might interfere with influenza invasion by interacting with HA protein.

Design, synthesis of oleanolic acid-saccharide conjugates using click chemistry methodology and study of their anti-influenza activity.

The development of entry inhibitors is an emerging approach to the inhibition of influenza virus. In our previous research, oleanolic acid (OA) was discovered as a mild influenza hemagglutinin (HA) inhibitor. Herein, as a further study, we report the preparation of a series of OA-saccharide conjugates via the CuAAC reaction, and the anti-influenza activity of these compounds was evaluated in vitro. Among them, compound 11b, an OA-glucose conjugate, showed a significantly increased anti-influenza activity with an IC50 of 5.47 µM, and no obvious cytotoxic effect on MDCK cells was observed at 100 µM. Hemagglutination inhibition assay and docking experiment indicated that 11b might interfere with influenza virus infection by acting on HA protein. Broad-spectrum anti-influenza experiments showed 11b to be robustly potent against 5 different strains, including influenza A and B viruses, with IC50 values at the low-micromole level. Overall, this finding further extends the utility of OA-saccharide conjugates in anti-influenza virus drug design.

The Shared Bicycle and Its Network-Internet of Shared Bicycle (IoSB): A Review and Survey.

With the expansion of Intelligent Transport Systems (ITS) in smart cities, the shared bicycle has developed quickly as a new green public transportation mode, and is changing the travel habits of citizens heavily across the world, especially in China. The purpose of the current paper is to provide an inclusive review and survey on shared bicycle besides its benefits, history, brands and comparisons. In addition, it proposes the concept of the Internet of Shared Bicycle (IoSB) for the first time, as far as we know, to find a feasible solution for those technical problems of the shared bicycle. The possible architecture of IoSB in our opinion is presented, as well as most of key IoT technologies, and their capabilities to merge into and apply to the different parts of IoSB are introduced. Meanwhile, some challenges and barriers to IoSB's implementation are expressed thoroughly too. As far as the advice for overcoming those barriers be concerned, the IoSB's potential aspects and applications in smart city with respect to technology development in the future provide another valuable further discussion in this paper.