Medical School of Kunming University of Science and Technology, Kunming, Yunnan 650500, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Bioorg Med Chem. 2019 Dec 1;27(23):115147. doi: 10.1016/j.bmc.2019.115147. Epub 2019 Oct 15.
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 IC 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.
病毒进入抑制剂在开发新一代抗流感药物的当前努力中具有重要意义。受一系列五环三萜衍生物作为针对流感病毒 HA 蛋白的进入抑制剂的发现启发，我们通过将不同的氨基酸连接到 OA 的 28-COOH 上，在本研究中设计并合成了 32 种齐墩果酸 (OA) 类似物。这些化合物的抗病毒活性在体外进行了评估。其中一些化合物对甲型流感病毒/WSN/33 (H1N1) 病毒表现出令人印象深刻的抗流感活性。其中，化合物 15a 表现出强大的活性和广谱抗病毒谱，对四种不同的流感株的 IC 值均在低微摩尔水平。血凝抑制 (HI) 试验和对接实验表明，这些 OA 类似物可能通过与流感病毒的 HA 蛋白结合，从而阻断病毒进入，通过与宿主细胞唾液酸受体的相互作用来发挥作用，就像它们的母体化合物一样。
