State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, United States.
Mol Pharm. 2020 Jul 6;17(7):2546-2554. doi: 10.1021/acs.molpharmaceut.0c00244. Epub 2020 Jun 1.
Naturally occurring pentacyclic triterpenes, such as betulinic acid (BA) and its derivatives, exhibit various pharmaceutical activities and have been the subject of great interest, in particular for their antiviral properties. Here, we found a new anti-influenza virus conjugate, hexakis 6-deoxy-6-[4--(3β-hydroxy-lup-20(29)-en-28-oate)aminomethyl-1-1,2,3-triazol-1-yl]-2,3-di--acetyl-α-cyclodextrin (CYY1-11, ), in a mini library of pentacyclic triterpene-cyclodextrin conjugates by performing a cell-based screening assay and then exploring the underlying mechanisms. Our results showed that conjugate possessed a high-level activity against the influenza virus A/WSN/33 with an IC value of 5.20 μM (SI > 38.4). The study of the mechanism of action indicated that conjugate inhibited viral replication by directly targeting the influenza hemagglutinin protein ( = 1.50 μM), thus efficiently preventing the attachment of the virion to its receptors on host cells and subsequent infection. This study suggests that multivalent BA derivatives have possible use as a new class of influenza virus entry inhibitors.
天然存在的五环三萜类化合物，如白桦脂酸（BA）及其衍生物，具有多种药物活性，一直是人们关注的焦点，特别是它们的抗病毒特性。在这里，我们通过细胞筛选实验从小环三萜类化合物-环糊精缀合物文库中发现了一种新的抗流感病毒缀合物，六（6-脱氧-6-[4--（3β-羟基-羊毛甾-20（29）-烯-28-酸）氨基甲基-1,2,3-三唑-1-基]-2,3-二-O-乙酰基-α-环糊精（CYY1-11，），并进一步探讨了其潜在的作用机制。结果表明，该缀合物对 A/WSN/33 流感病毒具有高活性，IC 值为 5.20 μM（SI > 38.4）。作用机制研究表明，该缀合物通过直接靶向流感血凝素蛋白（= 1.50 μM）抑制病毒复制，从而有效阻止病毒粒子与宿主细胞上的受体结合及随后的感染。本研究提示五环三萜类化合物的多价衍生物可能作为一类新型流感病毒进入抑制剂。
