title: Discovery of imidazo[2,1-b]thiazole HCV NS4B inhibitors exhibiting synergistic effect with other direct-acting antiviral agents.
abstract: The design, synthesis, and SAR studies of novel inhibitors of HCV NS4B based on the imidazo[2,1-b]thiazole scaffold were described. Optimization of potency with respect to genotype 1b resulted in the discovery of two potent leads 26f (EC50 = 16 nM) and 28g (EC50 = 31 nM). The resistance profile studies revealed that 26f and 28g targeted HCV NS4B, more precisely the second amphipathic α helix of NS4B (4BAH2). Cross-resistance between our 4BAH2 inhibitors and other direct-acting antiviral agents targeting NS3/4A, NS5A, and NS5B was not observed. For the first time, the synergism of a series of combinations based on 4BAH2 inhibitors was evaluated. The results demonstrated that our 4BAH2 inhibitor 26f was synergistic with NS3/4A inhibitor simeprevir, NS5A inhibitor daclatasvir, and NS5B inhibitor sofosbuvir, and it could also reduce the dose of these drugs at almost all effect levels. Our study suggested that favorable effects could be achieved by combining 4BAH2 inhibitors such as 26f with these approved drugs and that new all-oral antiviral combinations based on 4BAH2 inhibitors were worth developing to supplement or even replace current treatment regimens for curing HCV infection.
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Ning-Yu
authors.initials: NY
authors.lastname: Wang
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Wei-Qiong
authors.initials: WQ
authors.lastname: Zuo
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Kun-Jie
authors.initials: KJ
authors.lastname: Xiao
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.|‡Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.|‡Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
authors.forename: Xiu-Xiu
authors.initials: XX
authors.lastname: Zeng
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.|‡Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: You
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.|‡Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
authors.forename: Li-Dan
authors.initials: LD
authors.lastname: Zhang
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Zhi-Hao
authors.initials: ZH
authors.lastname: Liu
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Ting-Hong
authors.initials: TH
authors.lastname: Ye
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Song
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lei
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.|‡Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
authors.forename: Cui-Ting
authors.initials: CT
authors.lastname: Peng
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.affiliation: §State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D009154:Mutation; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C080107:NS4B protein, flavivirus; D013844:Thiazoles; D017361:Viral Nonstructural Proteins