Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seaso...Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.展开更多
New N-adamantyl-2-amino-acylamides（3a--3f） and N-adamantyl-2-phenoxy-acetamides（6a--6d） were designed and synthesized by the modification of the amino group of amantadine I and the structures were confirmed by mas...New N-adamantyl-2-amino-acylamides（3a--3f） and N-adamantyl-2-phenoxy-acetamides（6a--6d） were designed and synthesized by the modification of the amino group of amantadine I and the structures were confirmed by mass spectra（MS） and 1H NMR spectra. The antiviral potencies of the synthesized compounds were evaluated against the replication of influenza virus A/H3N2 subtype in Madin-Darby canine kidney（MDCK） cells. Among the amantadine derivatives, compound 3a bad the strongest antiviral potency and showed activity similar to that of amantadine. Interestingly, the bulky and extended lipophilic moieties on the a-position of the carbonyl group resulted in decreases in potency.展开更多
基金supported by the National Natural Science Foundation of China (81788101, 81573587 and 81490531)the Ministry of Science and Technology of China (2015CB5534/6)+3 种基金111 project (B08007)the Peking Union Medical College Youth FundFundamental Research Funds for Central Universities (3332013132)the CAMS Innovation Fund for Medical Sciences (2017-I2M-1-009)
文摘Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.
文摘New N-adamantyl-2-amino-acylamides（3a--3f） and N-adamantyl-2-phenoxy-acetamides（6a--6d） were designed and synthesized by the modification of the amino group of amantadine I and the structures were confirmed by mass spectra（MS） and 1H NMR spectra. The antiviral potencies of the synthesized compounds were evaluated against the replication of influenza virus A/H3N2 subtype in Madin-Darby canine kidney（MDCK） cells. Among the amantadine derivatives, compound 3a bad the strongest antiviral potency and showed activity similar to that of amantadine. Interestingly, the bulky and extended lipophilic moieties on the a-position of the carbonyl group resulted in decreases in potency.
