Specific inhibition of hepatitis C virus replication by cyclosporin A

Nakagawa, Mina; Sakamoto, Naoya; Enomoto, Nobuyuki; Tanabe, Yoko; Kanazawa, Nobuo; Koyama, Tomoyuki; Kurosaki, Masayuki; Maekawa, Shinya; Yamashiro, Tsuyoshi; Chen, Cheng Hsin; Itsui, Yasuhiro; Kakinuma, Sei; Watanabe, Mamoru

doi:10.1016/j.bbrc.2003.11.080

Cited by 215 publications

(183 citation statements)

References 34 publications

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“…17,18 Here we report on the potent anti-HCV activity of DEBIO-025, a non-immunosuppressive cyclosporin. Neither CsA nor DEBIO-025 proved active against other members of the family of the Flaviviridae, such as a pestvirus (the bovine viral diarrhea virus in MDBK) and a flavivirus [the yellow fever virus in Vero or HepG2 cells] (our unpublished data).…”

Section: Discussionmentioning

confidence: 98%

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The non‐immunosuppressive cyclosporin DEBIO‐025 is a potent inhibitor of hepatitis C virus replication in vitro†

et al. 2006

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Section: Discussionmentioning

confidence: 98%

“…16 Recently CsA was shown to exhibit anti-HCV activity in vitro. 17,18 In 1988, Teraoka and colleagues 19 reported that CsA had a beneficial effect on non-A, non-B hepatitis in two chimpanzees chronically infected with HCV. After treatment with CsA was terminated, the disease recurred in both chimpanzees.…”

mentioning

confidence: 99%

The non‐immunosuppressive cyclosporin DEBIO‐025 is a potent inhibitor of hepatitis C virus replication in vitro†

et al. 2006

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“…On the other hand, in vitro studies have previously demonstrated that CsA suppresses HCV replication, an effect not shared by tacrolimus. [11][12][13] Over the last 10 years, most trials comparing CsA-ME and tacrolimus in HCV-positive patients have enrolled fewer than 100 patients per treatment such that they were not powered to detect a difference in survival rates. Nevertheless, some authors have reported better outcomes in patients receiving CsA-ME.…”

Section: Discussionmentioning

confidence: 99%

12-month follow-up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

Levy¹,

Grazi²,

Mühlbacher³

et al. 2006

Liver Transpl

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The LIS2T study was an open-label, multicenter study in which recipients of a primary liver transplant were randomized to cyclosporine microemulsion (CsA-ME) (Neoral) (n ϭ 250) (monitoring of blood concentration at 2 hours postdose) C 2 or tacrolimus (n ϭ 245) (monitoring of trough drug blood level [predose]) C 0 to compare efficacy and safety at 3 and 6 months and to evaluate patient status at 12 months. All patients received steroids with or without azathioprine. At 12 months, 85% of CsA-ME patients and 86% of tacrolimus patients survived with a functioning graft (P not significant). Efficacy was similar in deceased-and living-donor recipients. Significantly fewer hepatitis C-positive patients died or lost their graft by 12 months with CsA-ME (5/88, 6%) than with tacrolimus (14/85, 16%) (P Ͻ 0.03). Recurrence of hepatitis C virus in liver grafts was similar in each group. Based on biopsies driven by clinical events, the mean time to histological diagnosis of hepatitis C virus recurrence was significantly longer with CsA-ME (100 Ϯ 50 days) than with tacrolimus (70 Ϯ 40 days) (P Ͻ 0.05). Median serum creatinine at 12 months was 106 mol/L with CsA-ME and with tacrolimus. More patients who were nondiabetic at baseline received antihyperglycemic therapy in the tacrolimus group at 12 months (13% vs. 5%, P Ͻ 0.01). Of patients who were diabetic at baseline, more tacrolimus-treated individuals required anti-diabetic treatment at 12 months (70% vs. 49%, P ϭ 0.02). Treatment for de novo or preexisting hypertension or hyperlipidemia was similar in both groups. In conclusion, the efficacy of CsA-ME monitored by blood concentration at 2 hours postdose and tacrolimus in liver transplant patients is equivalent to 12 months, and renal function is similar. More patients required antidiabetic therapy with tacrolimus regardless of diabetic status at baseline. Abbreviations: CsA-ME, cyclosporine microemulsion; CsA, cyclosporine; C 2, blood concentration at 2 hours postdose; HCV, hepatitis C virus; C 0, trough drug blood level (predose).

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“…However, FK506 lacks antiviral activity in the HCV replicon system. 7,12 Certain CsA analogs, such as NIM811 and DEBIO-025, have been shown to have potent anti-HCV activity. 9,13 These CsA analogs retain their ability to bind CyPs, but are no longer recognized by calcineurin.…”

Section: H Epatitis C Virus (Hcv) Chronically Infects Ap-mentioning

confidence: 99%

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

et al. 2007

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HCV reoccurs after liver transplantation and increases mortality. Cyclosporine, but not tacrolimus, has potent antiviral effects against HCV replication in cell culture. To determine the conditions, if any, under which HCV is susceptible to cyclosporine in vivo, we selected for cyclosporine-resistant mutant HCV in vitro. The resulting mutations were mapped to x-ray crystallographic structures and sequence databases. Mutations selected by cyclosporine were clustered in the nonstructural (NS) proteins NS5A and NS5B. Different sets of mutations in NS5A, paired with the same 2 NS5B mutations, conferred different levels of cyclosporine resistance when engineered back into the HCV replicon. Mutations in NS5B are structurally consistent with a proposed model of regulation of RNA binding by cyclophilin B (CyPB). These mutations also highlight a natural polymorphism between different HCV genotypes that correlates with the variation in response to cyclosporine A (CsA) noted in some clinical trials. Replicons engineered to have mutations in only NS5A (P < 0.0001) or only NS5B (P ‫؍‬ 0.002) suggest that while both NS5A or NS5B variants alter cyclosporine susceptibility, NS5A has the largest effect. Conclusion: Preexisting sequence variation could alter the effect of cyclosporine on HCV in vivo. (HEPATOLOGY

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Specific inhibition of hepatitis C virus replication by cyclosporin A

Cited by 215 publications

References 34 publications

The non‐immunosuppressive cyclosporin DEBIO‐025 is a potent inhibitor of hepatitis C virus replication in vitro†

The non‐immunosuppressive cyclosporin DEBIO‐025 is a potent inhibitor of hepatitis C virus replication in vitro†

12-month follow-up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

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