title: Oligothiophene compounds inhibit the membrane fusion between H5N1 avian influenza virus and the endosome of host cell.
abstract: Hemagglutinin (HA) which is essential for influenza viral infection and replication has become a target for the design of anti-influenza drugs. A novel series of oligothiophene compounds focused on the target were synthesized as specific inhibitors against the H5 subtype of influenza A viruses because oligothiophene has stronger π-π interactions with residues F1102and M241of HA2 side chains. Oligothiophene compounds were designed and synthesized by a series of alkylation, azidation, amination and amidation reactions. The entry inhibitory activities of those compounds were tested at a cellular level against H5N1 influenza pseudovirus. Compound 3sf was revealed as the most active inhibitor in this series with an IC50of 0.029 μM. The activity of 3sf is almost 1000 times that of the positive reference compound (CL-385319). A structure-activity analysis of these compounds demonstrated that the size of the oligothiophene compounds was very important for the inhibitory activity. Four compounds (3sk, 3sf, 3sc and 4sc) of strong inhibitiory activity against H5N1 influenza pseudovirus were assessed against H1N1 influenza virus MDCK. They also showed strong inhibitiory activity with IC50sof 3.292 μM, 1.240 μM, 1.119 μM and 0.768 μM, respectively.
authors.affiliation: Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key laboratory of New drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, PR China; Department of Chemistry, The Ohio State University, 100 W. 18th Ave. Columbus, Ohio 43210, USA.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, The Ohio State University, 100 W. 18th Ave. Columbus, Ohio 43210, USA.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key laboratory of New drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, PR China.
authors.forename: Xiantian
authors.initials: X
authors.lastname: Shen
authors.affiliation: Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key laboratory of New drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, PR China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA.
authors.forename: Xiangtao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Chemistry, The Ohio State University, 100 W. 18th Ave. Columbus, Ohio 43210, USA. Electronic address: parquett@chemistry.ohio-state.edu.
authors.forename: Jon R
authors.initials: JR
authors.lastname: Parquette
authors.affiliation: Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, Guangdong Provincial Key laboratory of New drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, PR China. Electronic address: liusw@smu.edu.cn.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D008561:Membrane Fusion / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D013876:Thiophenes
keywords: Fusion inhibitor; H5N1 influenza virus; Hemagglutinin(HA); Oligothiophene compounds