Combinations of Cyclophilin Inhibitor NIM811 with Hepatitis C Virus NS3-4A Protease or NS5B Polymerase Inhibitors Enhance Antiviral Activity and Suppress the Emergence of Resistance

Abstract

Chronic hepatitis C virus (HCV) infection remains a major global health burden while current interferon-based therapy is suboptimal. Efforts to develop more effective antiviral agents mainly focus on two viral targets: NS3-4A protease and NS5B polymerase. However, resistant mutants against these viral specific inhibitors emerge quickly both in vitro and in patients, particularly in the case of monotherapy. An alternative and complementary strategy is to target host factors such as cyclophilins that are also essential for viral replication. Future HCV therapies will most likely be combinations of multiple drugs of different mechanisms to maximize antiviral activity and to suppress the emergence of resistance. Here, the effects of combining a host cyclophilin inhibitor NIM811 with other viral specific inhibitors were investigated in vitro using HCV replicon. All of the combinations led to more pronounced antiviral effects than any single agent, with no significant increase of cytotoxicity. Moreover, the combination of NIM811 with a nucleoside (NM107) or a non-nucleoside (thiophene-2-carboxylic acid) polymerase inhibitor was synergistic, while the combination with a protease inhibitor (BILN2061) was additive. Resistant clones were selected in vitro with these inhibitors. Interestingly, it was much more difficult to develop resistance against NIM811 than viral specific inhibitors. No cross-resistance was observed among these inhibitors. Most notably, NIM811 was highly effective in blocking the emergence of resistance when used in combination with viral protease or polymerase inhibitors. Taken together, these results illustrate the significant advantages of combining inhibitors targeting both viral and host factors as key components of future HCV therapies.Hepatitis C virus (HCV) infection presents a significant global health challenge with approximately 170 million people or 3% of the world population chronically infected and an additional 3 to 4 million more people infected each year (according to World Health Organization estimates). Although only 25% of new infections are symptomatic, 60 to 80% of patients develop chronic liver disease, of whom an estimated 20% progress to cirrhosis with a 1 to 4% annual risk of developing hepatocellular carcinoma (19). Overall, HCV is responsible for 50 to 76% of all liver cancer cases and two-thirds of all liver transplants in developed countries. Ultimately, 5 to 7% of infected patients will die from the consequences of HCV infection (according to World Health Organization estimates).The current standard therapy for HCV infection is pegylated alpha interferon (IFN-␣) in combination with ribavirin. However, fewer than 50% of patients with genotype 1 virus, the predominant HCV genotype in developed countries, are successfully treated with IFN-based therapies. Moreover, both IFN and ribavirin induce significant adverse effects, including flu-like symptoms (fever and fatigue), hematologic complications (leukopenia, thrombocytopenia), and neuropsychiatric issues (depression, insomn...

MK-7009, a Potent and Selective Inhibitor of Hepatitis C Virus NS3/4A Protease

“…NS3/4A protease inhibitors have previously been shown to demonstrate synergy with agents acting via multiple other mechanisms, including peginterferon alfa 2a (20,45), NS5B polymerase inhibitors (7,14), NS4A antagonists (53), and cyclosporine analogs (3,30). In the short term, they may allow a reduced duration of therapy when they are used in combination with interferon and ribavirin, coupled with improved SVR rates, particularly in difficult-to-treat genotype 1-infected patients.…”

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

“…These compounds are thought to partially inhibit HCV replication by binding to cyclophilin A and possibly other cyclophilins, of which there are at least 16 expressed in mammalian cells [115][116][117]. Additional studies suggest that co-treatment with cyclophilin inhibitors and protease or polymerase inhibitors leads to a reduction in HCV replication and limits development of resistance to monotherapy alone [117][118][119][120].…”

Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication

“…To determine whether the enzymatic activity of PIK4 enzymes was critical for their role in HCV replication, the activity of a known pharmacological PI4KB inhibitor, PIK93, was examined in the Luc-1b, Luc-1a, and JFH1-2a assays (58,72). The activity of PIK93 was compared to the cyclophilin inhibitor NIM811 (Table 2) (38). The cyclophilin inhibitor NIM811 has been reported to inhibit HCV replication in vitro and is currently in clinical trials as a novel anti-HCV therapy (40).…”