Design,synthesis and biological evaluation of amino acids-oleanolic acid conjugates as influenza virus inhibitors |
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| Affiliation: | 1. Medical School of Kunming University of Science and Technology, Kunming, Yunnan 650500, China;2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;3. Faculty of Life Science and Technology of Kunming University of Science and Technology, Kunming, Yunnan 650500, China;1. Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China;2. State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China;3. Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China;4. Department of Cardiology, First People’s Hospital of Yancheng, Fourth Affiliated Hospital of Nantong University, Yancheng 224005, China;1. Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze, ed. 17, I-90128 Palermo, Italy;2. Centro Grandi Apparecchiature (CGA) – ATeN Center, University of Palermo, via F. Marini 14, 90128 Palermo, Italy;3. Dipartimento di Scienze Agrarie, Alimentari e Forestali (SAAF), Università degli Studi di Palermo, Viale delle Scienze, ed. 4, I-90128 Palermo, Italy;1. Department of Computer Science, City University of Hong Kong, Hong Kong Special Administrative Region;2. Department of Chemistry, City University of Hong Kong, Hong Kong Special Administrative Region;1. Department of Pharmaceutical Engineering, Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, PR China;2. Faculty of Chemical & Environmental Engineering, Wuyi University, Jiangmen 529020, PR China |
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| Abstract: | 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. |
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| Keywords: | Influenza A virus Entry inhibitor Oleanolic acid Amino acids Hemagglutinin |
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