In vitro combinations containing Tegobuvir are highly efficient in curing cells from HCV replicon and in delaying/preventing the development of drug resistance

Abstract

Tegobuvir (GS-9190) is a non-nucleoside inhibitor of HCV RNA replication with proven antiviral activity in HCV-infected patients. The in vitro antiviral activity of Tegobuvir, when combined with one or two other direct acting antivirals (DAA) was assessed. When Tegobuvir was combined with either interferon α-2b, ribavirin, the protease inhibitor (PI) VX-950, the nucleoside polymerase inhibitor (NI) 2'-C-methylcytidine or various non-nucleoside polymerase inhibitors, an overall additive antiviral activity was observed. Adding Tegobuvir (at concentrations of 6, 30 or 150nM) to replicon-containing cells in the presence of suboptimal concentrations of the PI or of the various polymerase inhibitors either markedly delayed or completely prevented resistance development against these latter compounds. Tegobuvir (15nM), when combined with the PI, was able to cure replicon-containing cells from their replicon after a single passage, whereas either compound alone (at 2-fold higher concentration) was not. The triple combination of Tegobuvir (10nM), the PI and the NI resulted in clearance of replicon RNA after only two passages. In contrast, the inhibitors when used alone at 3-fold higher concentrations were not able to cure the cells from the replicon, after as long as 6 passages. Combinations containing low concentrations of Tegobuvir are thus highly effective in curing cells from HCV replicon and in delaying or preventing the development of resistance against other DAA.

Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2

“…Tegobuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) RNA replication with proven antiviral activity in the patients suffering from chronic genotype 1 HCV infection. Tegobuvir is an analog of imidazopyridine class inhibitors that selectively targets HCV (Vliegen et al., 2015 ). However, the most common side effects of Tegobuvir includes cough, dizziness, fatigue and dry mouth (Vliegen et al., 2015 ).…”

Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

“…In a trial of tegobuvir with a protease inhibitor, GS-9256, the majority of GT1a patients developed double-resistance mutations for these DAAs, with Y448H detected in seven out of eight GT1a patients, while RAVs C316Y and C445F were also detected in two GT1b patients [ 104 ]. The clinical development of tegobuvir was recently halted; however, an in vitro study recently demonstrated the potential of tegobuvir as a DAA due to its additive effect when examined with PIs or NNIs in inhibiting replicon models and significantly hindering the development of resistance mutations [ 105 ].…”

Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence

“…Using mathematical models, we showed that superinfection and cure of infected cells are likely to be crucial mechanisms driving the extremely rapid expansion and turnover of resistant variants observed in the clinical data. Although superinfection and cure of infected cells have been demonstrated in vitro ( 33 – 37 , 41 ), our work suggests that these processes occur and play important roles in driving viral adaptation and persistence in vivo.…”

“…In addition, we hypothesize that the continuous turnover of dominant mutants in the absence of treatment is mostly driven by intracellular competition among viral strains, as a result of superinfection (rather than competition for newly generated target cells). Previously, cure of infected cells has been demonstrated in in vitro studies ( 33 – 37 ). In vivo, the rapid second-phase viral declines under treatment were suggested to be attributable to cure of infected cells ( 32 , 38 ).…”