Evaluation of Antiviral Drug Synergy in an Infectious HCV System

Abstract

Background Direct-acting antivirals (DAAs) have greatly improved the treatment of HCV infection. To improve response and prevent resistance, combination regimens have been the focus of clinical development. Regimens are often first assessed in vitro, with most combination studies to date using subgenomic replicon systems, which do not replicate the complete HCV life cycle and preclude study of entry and assembly inhibitors. Infectious full-length HCV systems have been developed and are being used to test drug efficacy. Methods Using cell-based HCV Con1b replicon and an infectious full-length HCV (HCVcc-Luc) infection system, we systematically tested the synergy, additivity or antagonism of combinations of protease, NS5A and nucleotide NS5B inhibitor classes as well as the combination of these DAAs with host-targeting agent cyclosporin A or non-antibody entry inhibitor (S)-chlorcyclizine. Two computational software packages, MacSynergyII and CalcuSyn, were used for data analysis. Results Combinations between different classes showed good consistency across the two viral assay systems and two software platforms. Combinations between NS5A and nucleotide NS5B inhibitors were synergistic, while combinations of protease inhibitors with the other two classes were additive to slightly antagonistic. As expected, combinations of antivirals of the same class were additive. Combination studies between these DAA classes and cyclosporin A or (S)-chlorcyclizine demonstrated additive to synergistic effects and highly synergistic effects, respectively. Combinations of these drugs did not show any added or unexpected cytotoxicity. Conclusions Our results show that in vitro combination studies of anti-HCV DAAs in the HCVcc system may provide useful guidance for drug combination designs in clinical studies. We also demonstrate that these DAAs in combination with host-targeting agents or entry inhibitors may improve HCV treatment response.

Computational screening of medicinal plant phytochemicals to discover potent pan-serotype inhibitors against dengue virus

“…This is particularly important against viruses which keep evolving continuously due to higher rate of mutation. The benefit of treatment strategies involving synergism has been already reported in case of HIV and HCV infections 47,48 . These inhibitors may lead to one therapeutic solution against the diversity of DV serotypes by efficiently targeting and inhibiting the catalytic function of three functionally conserved non-structural proteins.…”

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

“…This is critically important against constantly evolving CoVs. The benefits of treatment strategies involving pan-inhibitors have already been reported in the case of Dengue virus [ 28 , 117 ], HCV [ [118] , [119] , [120] , [121] ], and HIV [ 122 ]. The screened inhibitors in the present study may lead towards a medicinal solution against the variety of constantly evolving CoVs by effectively targeting/hindering the proteolytic role of their PL pro .…”

Preclinical Pharmacological Development of Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection

“…Advancements in HCV cell culture systems allowed us to approach this problem from a phenotypic perspective, to develop treatments that have a different mode of action from the existing DAAs, and are thus likely synergistic with currently available drugs due to their mechanism of action [21][22][23]. We have previously shown that CCZ inhibits the entry step of HCV infection and exhibits synergistic activity with currently approved anti-HCV agents in vitro [14,24]. The mechanism of action of CCZ and related compounds has been proposed to target the fusion process of viral entry, possibly involving the fusion loop sequence of the HCV E1 protein [25].…”