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 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.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , 38 Xueyuan Road, Beijing 100191, China.
Maorong
M
Yu
Longlong
L
Si
Yufei
Y
Wang
Yiming
Y
Wu
Fei
F
Yu
Pingxuan
P
Jiao
Yongying
Y
Shi
Han
H
Wang
Sulong
S
Xiao
Ge
G
Fu
Ke
K
Tian
Yitao
Y
Wang
Zhihong
Z
Guo
Xinshan
X
Ye
Lihe
L
Zhang
Demin
D
Zhou
D000281:Administration, Intranasal; D000818:Animals; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis*
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D014315:Triterpenes