Synthesis of a Hexavalent Betulinic Acid Derivative as a Hemagglutinin-Targeted Influenza Virus Entry Inhibitor

• Published in: Molecular pharmaceutics Vol. 17; no. 7; pp. 2546 - 2554
• Main Authors: Chen, Yingying, Wang, Xinchen, Zhu, Yinbiao, Si, Longlong, Zhang, Bo, Zhang, Yongmin, Zhang, Lihe, Zhou, Demin, Xiao, Sulong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.07.2020
• Subjects: A549 Cells; Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Biochemistry, Molecular Biology; Cyclodextrins - chemistry; Dogs; Hemagglutinins - chemistry; Hemagglutinins - metabolism; Humans; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H1N1 Subtype - metabolism; Influenza A Virus, H1N1 Subtype - pathogenicity; Influenza, Human - drug therapy; Inhibitory Concentration 50; Life Sciences; Madin Darby Canine Kidney Cells; Mass Spectrometry; Pentacyclic Triterpenes - chemistry; Protein Binding; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Triazoles - therapeutic use; Virus Internalization - drug effects; entry inhibitor; influenza virus; betulinic acid; α-cyclodextrin
• ISSN: 1543-8384; 1543-8392; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.0c00244

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-N-(3β-hydroxy-lup-20­(29)-en-28-oate)­aminomethyl-1H-1,2,3-triazol-1-yl]-2,3-di-O-acetyl-α-cyclodextrin (CYY1-11, 1), 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 1 possessed a high-level activity against the influenza virus A/WSN/33 with an IC50 value of 5.20 μM (SI > 38.4). The study of the mechanism of action indicated that conjugate 1 inhibited viral replication by directly targeting the influenza hemagglutinin protein (K D = 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.