Discovery of Pentacyclic Triterpenoids as Potential Entry Inhibitors of Influenza Viruses

Entry inhibitors are of particular importance in current efforts to develop a new generation of anti-influenza virus drugs. Here we report certain pentacyclic triterpenes exhibiting conserved structure features and with in vitro anti-influenza virus activity comparable to and even higher than that o...

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Published inJournal of medicinal chemistry Vol. 57; no. 23; pp. 10058 - 10071
Main Authors Yu, Maorong, Si, Longlong, Wang, Yufei, Wu, Yiming, Yu, Fei, Jiao, Pingxuan, Shi, Yongying, Wang, Han, Xiao, Sulong, Fu, Ge, Tian, Ke, Wang, Yitao, Guo, Zhihong, Ye, Xinshan, Zhang, Lihe, Zhou, Demin
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 11.12.2014
Amer Chemical Soc
Subjects
Administration, Intranasal
Animals
Chemistry, Medicinal
HEK293 Cells
Hemagglutinin Glycoproteins, Influenza Virus - chemistry
Humans
Influenza A virus - drug effects
Influenza A virus - metabolism
Life Sciences & Biomedicine
Mice, Inbred BALB C
Models, Molecular
Pharmacology & Pharmacy
Science & Technology
Structure-Activity Relationship
Triterpenes - chemical synthesis
A VIRUS
MEMBRANE-FUSION
REPLICATION
PEPTIDES
ACID
MECHANISM
AVIAN INFLUENZA
INFECTION
OLEANANE-TYPE TRITERPENES
RECEPTOR-BINDING
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Summary:Entry inhibitors are of particular importance in current efforts to develop a new generation of anti-influenza virus drugs. Here we report certain pentacyclic triterpenes exhibiting conserved structure features and with in vitro anti-influenza virus activity comparable to and even higher than that of oseltamivir. Mechanistic studies indicated that these lead triterpenoids bind tightly to the viral envelope hemagglutinin (HA), disrupting the interaction of HA with the sialic acid receptor and thus the attachment of viruses to host cells. Docking studies suggest that the binding pocket within HA for sialic acid receptor potentially acts as a targeting domain, and this is supported by structure–activity data, sialic acid competition studies, and broad anti-influenza spectrum as well as less induction of drug resistance. Our study might establish the importance of triterpenoids for development of entry inhibitors of influenza viruses.
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ISSN:0022-2623
1520-4804
DOI:10.1021/jm5014067