A high throughput screen of the Pfizer compound collection was carried out using a hepatitis C virus (HCV) genotype 1b subgenomic replicon cell line. Those confirmed hits that demonstrated broad spectrum activity with...A high throughput screen of the Pfizer compound collection was carried out using a hepatitis C virus (HCV) genotype 1b subgenomic replicon cell line. Those confirmed hits that demonstrated broad spectrum activity without overt cytotoxicity were further evaluated, leading to the identification of a series of pyrrolopyridines with excellent antiviral activity in a fully infectious HCV cell-based assay and pharmacokinetic properties.展开更多
Objective： The combination of interferon （IFN） and ribavirin （RBV） is the standard therapy for hepatitis C virus （HCV） infection. HCV genotype 2a has proved more amenable to the therapy, but its efficacy is yet...Objective： The combination of interferon （IFN） and ribavirin （RBV） is the standard therapy for hepatitis C virus （HCV） infection. HCV genotype 2a has proved more amenable to the therapy, but its efficacy is yet fimited. This study aimed to investigate the mechanism of the poor response in a case ofHCV genotype 2a infection. Methods： We analyzed dynamic change of HCV RNA from a patient, infected with HCV genotype 2a, showing a poor virological response to 1FN/RBV as judged 12 weeks after initiation of the therapy by HCV clone sequencing. Then we constructed subgenomic Japanese fulminant hepatitis-1 （JFH1） replicon and different chimeric replicons with humanized Gaussia luciferase gene. The chimeric replicons were derived from subgenomic JFH1 replicon, in which the NS5A region was replaced by the patient＇s sequence from the pre/post- treatment, and the chimeric replicons＇ susceptibility to IFN were evaluated by relative Gausia Luciferase activity. Results： The pretreatment HCV sequences appeared almost uniform, and the quasispecies variation was further more simplified after 12 weeks of therapy. Besides, the quasispecies variation seemed to be more diversified in the NS5A, relatively, a region crucial for IFN response, and each of chimeric replicons exhibited distinct response to IFN. Conclusions： During the course of the chronic infection, HCV population seems to be adapted to the patient＇s immunological system, and further to be selected by combination of 1FN/RBV therapy, indicating quasispecies may completely eliminated by addition of other drugs with targets different from those of IFN. In addition, each different response of chimeric replicon to IFN is most likely related to amino acid changes in or near the IFN-sensitivity determining region （ISDR） of NSSA during chronic infection and IFN/RBV therapy.展开更多
丙型肝炎病毒(Hepatitis C virus,HCV)感染的持久性引发慢性肝病疾病,并可能发展成为肝硬化和肝癌。目前对HCV的治疗不能达到理想的治疗效果,所以开发新型抗HCV药物迫在眉睫。抗HCV药物筛选的细胞模型,如复制子系统、假病毒系统、细胞...丙型肝炎病毒(Hepatitis C virus,HCV)感染的持久性引发慢性肝病疾病,并可能发展成为肝硬化和肝癌。目前对HCV的治疗不能达到理想的治疗效果,所以开发新型抗HCV药物迫在眉睫。抗HCV药物筛选的细胞模型,如复制子系统、假病毒系统、细胞培养系统,动物模型,如黑猩猩、uPA-SCID小鼠等,取得了快速的进展,并推动丙型肝炎的研究和抗HCV药物的发现。展开更多
文摘A high throughput screen of the Pfizer compound collection was carried out using a hepatitis C virus (HCV) genotype 1b subgenomic replicon cell line. Those confirmed hits that demonstrated broad spectrum activity without overt cytotoxicity were further evaluated, leading to the identification of a series of pyrrolopyridines with excellent antiviral activity in a fully infectious HCV cell-based assay and pharmacokinetic properties.
文摘Objective： The combination of interferon （IFN） and ribavirin （RBV） is the standard therapy for hepatitis C virus （HCV） infection. HCV genotype 2a has proved more amenable to the therapy, but its efficacy is yet fimited. This study aimed to investigate the mechanism of the poor response in a case ofHCV genotype 2a infection. Methods： We analyzed dynamic change of HCV RNA from a patient, infected with HCV genotype 2a, showing a poor virological response to 1FN/RBV as judged 12 weeks after initiation of the therapy by HCV clone sequencing. Then we constructed subgenomic Japanese fulminant hepatitis-1 （JFH1） replicon and different chimeric replicons with humanized Gaussia luciferase gene. The chimeric replicons were derived from subgenomic JFH1 replicon, in which the NS5A region was replaced by the patient＇s sequence from the pre/post- treatment, and the chimeric replicons＇ susceptibility to IFN were evaluated by relative Gausia Luciferase activity. Results： The pretreatment HCV sequences appeared almost uniform, and the quasispecies variation was further more simplified after 12 weeks of therapy. Besides, the quasispecies variation seemed to be more diversified in the NS5A, relatively, a region crucial for IFN response, and each of chimeric replicons exhibited distinct response to IFN. Conclusions： During the course of the chronic infection, HCV population seems to be adapted to the patient＇s immunological system, and further to be selected by combination of 1FN/RBV therapy, indicating quasispecies may completely eliminated by addition of other drugs with targets different from those of IFN. In addition, each different response of chimeric replicon to IFN is most likely related to amino acid changes in or near the IFN-sensitivity determining region （ISDR） of NSSA during chronic infection and IFN/RBV therapy.
文摘丙型肝炎病毒(Hepatitis C virus,HCV)感染的持久性引发慢性肝病疾病,并可能发展成为肝硬化和肝癌。目前对HCV的治疗不能达到理想的治疗效果,所以开发新型抗HCV药物迫在眉睫。抗HCV药物筛选的细胞模型,如复制子系统、假病毒系统、细胞培养系统,动物模型,如黑猩猩、uPA-SCID小鼠等,取得了快速的进展,并推动丙型肝炎的研究和抗HCV药物的发现。
