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Fluoxazolevir inhibits hepatitis C virus infection in humanized chimeric mice by blocking viral membrane fusion

Abstract

Fluoxazolevir is an aryloxazole-based entry inhibitor of hepatitis C virus (HCV). We show that fluoxazolevir inhibits fusion of HCV with hepatic cells by binding HCV envelope protein 1 to prevent fusion. Nine of ten fluoxazolevir resistance-associated substitutions are in envelope protein 1, and four are in a putative fusion peptide. Pharmacokinetic studies in mice, rats and dogs revealed that fluoxazolevir localizes to the liver. A 4-week intraperitoneal regimen of fluoxazolevir in humanized chimeric mice infected with HCV genotypes 1b, 2a or 3 resulted in a 2-log reduction in viraemia, without evidence of drug resistance. In comparison, daclatasvir, an approved HCV drug, suppressed more than 3 log of viraemia but is associated with the emergence of resistance-associated substitutions in mice. Combination therapy using fluoxazolevir and daclatasvir cleared HCV genotypes 1b and 3 in mice. Fluoxazolevir combined with glecaprevir and pibrentasvir was also effective in clearing multidrug-resistant HCV replication in mice. Fluoxazolevir may be promising as the next generation of combination drug cocktails for HCV treatment.

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Fig. 1: Fluoxazolevir disrupts HCV membrane fusion.
Fig. 2: Fluoxazolevir-resistant HCV substitutions generated from the in vitro resistance selection assay.
Fig. 3: Dose–response curves of fluoxazolevir against various chimeric HCV genotypes.
Fig. 4: Efficacy of fluoxazolevir in vivo against HCV genotypes 1b, 2a and 3 and multidrug-resistant HCV infection in Alb-uPA/Scid mice.

Data availability

The data used to generate the HCV E1 alignment in Fig. 2b and support the findings of this study are available from the Virus Pathogen Resource database (genotypes 1–6). The two genotype 7 sequences are available in the National Center for Biotechnology Information with accession nos. YP_009272536 and ARB18146. The source data for Figs. 1b,d–f, 3 and 4, and Extended Data Figs. 1b, 2, 3b,c and 410 are included in the article. Other data supporting the findings of this study are available from the corresponding author upon request.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and National Center for Advancing Translational Sciences, NIH, the Molecular Libraries Initiative funding to the University of Kansas Specialized Chemistry Center (grant no. U54HG005031) and the Japan Agency for Medical Research and Development (grant no. JP18fk0210020h0002).

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Authors

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T.J.L., C.D.M., Z.H. and K.J.F. conceptualized and designed the study. C.D.M., M.I., D.C.T., A.R., X.X., A.Q.W., D.L., T.U., M.O., Y.T., K.L., X.H., S.B.P., N.C., P.H.I., A.E.D., N.S., J.J.M., Z.H., K.C. and K.J.F. performed, analysed and contributed to all the experiments. C.D.M., Z.H. and T.J.L. wrote the manuscript. All other authors reviewed and contributed to the manuscript.

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Correspondence to Tsanyang Jake Liang.

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Extended data

Extended Data Fig. 1 Synthesis, efficacy, and photolysis of the fluoxazolevir-diazirine-biotin probe.

a, The general synthetic scheme of the fluoxazolevir-diazirine-biotin (fluoxazolevir-DB) probe is shown. Each intermediate was confirmed with 1H NMR and LCMS. See supplemental document for more information on each synthetic step. b, Fluoxazolevir-DB probe retains anti-HCV activity in vitro and shows inhibition against HCV infection in a dose-dependent manner. Data are presented as mean values ± SEM of 6 biologically independent replicates. c, The degradation of fluoxazolevir-DB via UV irradiation is shown. d, The fluoxazolevir-DB was exposed to UV irradiation with a 100 W mercury lamp with a 365 nm bypass filter. Disappearance of fluoxazolevir-DB was measured over time via LCMS and underwent a complete conversion to the carbene insertion product within 10 min. All results are representative of three independent experiments.

Source data

Extended Data Fig. 2 Dose-response curves of fluoxazolevir against amplified HCV from the in vitro drug resistance selection assay.

Among the 8 serial passages with potential RAS-containing HCV generated from the drug resistance selection assay (Fig. 2a), the viruses in the following wells (and their identified mutations) showed moderate resistance with EC50 values increasing by at least two-fold comparing to the wild-type control: A1 (F291L, V414A), B1 (I374T), C1 (D382E, T395A, M405V, P616A), E1 (F291V), G1 (A274S) and H1 (M267V, V284A). The same viruses were tested against sofosbuvir as a control and were equally sensitive to sofosbuvir as the wild type virus. Data are presented as mean values ± SEM of 3 biologically independent replicates. All results are representative of three independent experiments.

Source data

Extended Data Fig. 3 Viral fitness of the generated RAS-containing HCV.

a, The viral fitness assay scheme is shown here. Huh7.5.1 cells were electroporated with the RNA of each HCV RAS-RLuc construct. b, The first part of the assay assesses the replication capacity for each RAS-containing HCV. Luminescence was measured 4 h and 3 days after electroporation and the readings obtained 4 h after electroporation was used as background. c, The second part of the assay assesses infectivity of each RAS. Viral medium harvested 3 days after electroporation from part b was used to reinfect 104 naïve Huh7.5.1 cells in a 96-well plate. Luminescence was measured 48 h after reinfection and all measurements were normalized to HCV-WT. Data are presented as mean values ± SEM of 3 biologically independent replicates. All results are representative of three independent experiments.

Extended Data Fig. 4 Dose-response curves of fluoxazolevir against HCV mutants with putative RASs in core, E1 and E2 regions.

Huh7.5.1 cells in 96-well plates were infected with wild-type HCV-RLuc (GT 2a) and HCV-RLuc mutants with various putative RASs (R9G, V140L, M267V, A274S, V284A, F291L, F291V, I374T, D382E, T395A, M405V, V414A and P616A) in the presence of various fluoxazolevir concentrations as indicated. Cells were harvested 48 h after infection and luminescence assessed via the luciferase assay. The EC50 values for wild-type HCV-RLuc (black circles) and the HCV mutants (red squares) were calculated with Prism 7. Data are presented as mean values ± SEM of 8 biologically independent replicates. All results are representative of three independent experiments.

Source data

Extended Data Fig. 5 Cytotoxicity of fluoxazolevir against primary human hepatocytes, HepG2 cells, MT-4 cells and peripheral blood mononuclear cells.

Cells were treated with fluoxazolevir for 3 days and processed for the ATPlite cytotoxicity assay. CC50 values were calculated with the software, Prism 7. Data are presented as mean values ± SEM of 3 biologically independent replicates. All results are representative of three independent experiments.

Source data

Extended Data Fig. 6 Pharmacokinetics of fluoxazolevir.

Pharmacokinetic studies of fluoxazolevir were performed in (a) male CD-1 mouse, (b) male SD rat and (c) male beagle dog models (n = 3 animals). The concentration profiles of fluoxazolevir were measured after either a single PO dose of 10 mg/kg or a single IV dose of 3 mg/kg. Compound concentrations were measured by UPLC-MS/MS. d, Serum alanine aminotransferase (ALT) levels were measured in each animal model to assess the potential toxicity of fluoxazolevir in vivo. For CD-1 mice and SD rats, ALTs from the 10 mg/kg PO groups were shown, and for beagle dogs, the 3 mg/kg IV group was shown. Data are presented as mean values ± standard deviations.

Source data

Extended Data Fig. 7 Tissue distribution of fluoxazolevir after PO administration in rodents.

1The plasma and tissue concentrations of fluoxazolevir were measured after a single PO dose of fluoxazolevir. Thirty-nine mice and fifteen rats (n = 3/time point) for tissue collection. 2 AUC0-∞: area under the curve from zero to infinity; t1/2: half-life; Tmax: time to reach the maximal concentration; Cmax: maximal concentration after PO administration.

Source data

Extended Data Fig. 8 Maximal tolerable dose of fluoxazolevir in mice.

The study was performed by Pharmaron Inc. (Beijing, PR China). Single doses of fluoxazolevir (50 mg/kg, 100 mg/kg, 500 mg/kg and 1000 mg/kg) were administered via oral gavage to CD-1 mice (n = 3 mice per group) and observed for 3 days. Body weights of all animals were recorded daily. All study animals were monitored behavior such as respite, food and water consumption (by cage side checking), circling, eye/hair matting and any other abnormal effect. Any mortality and/or abnormal clinical signs were recorded. All animals were sacrificed for necropsy on day 3. Data are presented as mean values ± SEM.

Source data

Extended Data Fig. 9 Lack of toxicity of fluoxazolevir monotherapy in genotypes 1b, 2a and 3-infected Alb-uPA/Scid mice.

The body weights of the humanized Alb-uPA/Scid mice infected with HCV genotypes (a) 1b (n = 2-4 mice), (b) 2a (n = 3-4 mice) and (c) 3 (n = 3 mice) were monitored during and after fluoxazolevir treatment as described in Fig. 4a, b, Supplementary Figure 35. All mice in each group were weighed regularly for evidence of toxicity.

Source data

Extended Data Fig. 10 HCV RNA and serum human albumin levels of mice infected with multidrug-resistant HCV.

Humanized Alb-uPA/Scid mice were infected with the multidrug-resistant HCV strain and were either untreated (n = 4 mice) or treated with fluoxazolevir (n = 5 mice), GLE/PIB (n = 4 mice) or combination (n = 5 mice). Serum HCV RNA and human serum albumin levels were monitored weekly. a, Serum HCV RNA levels of untreated humanized Alb-uPA/Scid mice showed steady levels during follow-up. Time 0 is comparable to the time of initiation of treatment in (b). Mouse serum samples at the end of the 20 weeks were sequenced and the same NS3 and NS5a mutations as the inoculum virus were identified. b, Human serum albumin levels of untreated mice and mice treated with fluoxazolevir (5 mg/kg), glecaprevir (60 mg/kg) and pibrentasvir (24 mg/kg). Weekly serum levels of human albumin of individual mice were plotted. Weekly HCV RNA measurements of individual mice for each time point are shown in Fig. 4c. Serum human albumin graphs that end before the 10 weeks are due to death of the mice.

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Ma, C.D., Imamura, M., Talley, D.C. et al. Fluoxazolevir inhibits hepatitis C virus infection in humanized chimeric mice by blocking viral membrane fusion. Nat Microbiol 5, 1532–1541 (2020). https://doi.org/10.1038/s41564-020-0781-2

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