Poster Presentation 8th Australasian Virology Society Meeting and 11th Annual Meeting of the Australian Centre for Hepatitis & HIV Virology Meeting 2015

Non-Nucleoside Polymerase Inhibitors for Caliciviruses (#170)

Natalie Netzler 1 , Daniel Enosi Tuipulotu 1 , Auda Eltahla 2 , Jennifer Lun 1 , Nadya Urakova 3 4 5 , Michael Frese 3 4 5 6 , Tanja Strive 3 4 6 , Andrew Kelly 1 , Peter White 1
  1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
  2. Systems Medicine, Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  3. CSIRO Health and Biosecurity, CSIRO, Canberra, ACT, Australia
  4. Invasive Animals Cooperative Research Centre, University of Canberra, Canberra, ACT, Australia
  5. Health Research Institute, University of Canberra, Canberra, ACT, Australia
  6. Institute for Applied Ecology, University of Canberra, Canberra, ACT, Australia

Caliciviruses cause significant human and mammalian diseases, yet there are no calicivirus-specific antivirals available. Human norovirus (NoV) creates a substantial health burden, causing an estimated 230,000 deaths annually. Following years of intensive hepatitis C virus (HCV) research there are now 11 approved HCV antivirals available and their repurposing should be considered. These include an approved first-in-class non-nucleoside inhibitor (NNI) for class IV viruses, which targets the RNA-dependent RNA polymerase (RdRp), an essential viral replication enzyme. This study investigated the broad-spectrum antiviral activity of both HCV and NoV NNIs for treating caliciviruses.

Using a quantitative fluorescence-based RdRp assay, we identified broad-spectrum anti-calicivirus activities of four compounds: NIC02, JTK-109, TMC-647055 and Beclabuvir. NIC02 (RdRp motif B binder) is in pre-clinical studies, whilst JTK-109 (thumb I binder) development was halted in 2007 following phase II trials. However JTK-109 derivatives TMC-647055 and Beclabuvir have now advanced to phase II and III trials, respectively. Representative viruses from the Norovirus, Sapovirus and Lagovirus genera were all inhibited by JTK-109 (IC50 range: 7.6 µM – 16.6 µM) and NIC02 (IC50 range: 5.0 µM – 19.9 µM). When NIC02 and JTK109 were examined together, the two molecules exhibited combinational synergy against the NoV RdRp (CI value: 0.84). Additionally NIC02 demonstrated inhibition of two other genetically diverse RdRps; bacteriophage Φ6 RdRp (IC50 12.7 µM) and HCV RdRp (IC50 5.9 µM). Interestingly, the NoV RdRp was also susceptible to inhibition by TMC-647055 (IC50 28.3 µM) and Beclabuvir (IC50 23.8 µM). In summary, this study identified broad-spectrum NNIs which have potential as scaffolds for developing antivirals to treat calicivirus infections.