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

Purification, biochemical characterisation and identification of non-nucleoside inhibitors of the rabbit haemorrhagic disease virus polymerase (#209)

Nadya Urakova 1 2 3 , Natalie Netzler 4 , Andrew Kelly 4 , Michael Frese 1 2 3 5 , Peter White 4 , Tanja Strive 1 3 5
  1. CSIRO Health & Biosecurity, Canberra, ACT, Australia
  2. Health Research Institute, University of Canberra, Canberra, ACT, Australia
  3. Invasive Animals Cooperative Research Centre, Canberra, ACT, Australia
  4. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
  5. Institute for Applied Ecology, University of Canberra, Canberra, ACT

Rabbit haemorrhagic disease virus (RHDV) is a calicivirus that causes acute and often lethal infections in both wild and domestic European rabbits (Oryctolagus cuniculus). In Europe, RHDV is responsible for significant economic losses in rabbit farming. The virus also has a negative effect on wild rabbit populations and predators that rely on rabbits as food. In Australia, RHDV is used as a biocontrol agent for the management of feral rabbit populations and represents a significant threat for commercially valuable rabbit stocks and pets. Recently, an antigenic variant of RHDV (termed RHDV2) has emerged in Europe and has been reported to overcome immune protection from commercially available vaccines. This emphasises a need for the development of universally effective antiviral agents to protect both high value rabbit breeding stocks and valued family pets, until a new vaccine is developed and becomes available.

RNA-dependent RNA polymerases (RdRps) play a critical role in the replication cycle of almost all RNA viruses, which makes them a primary target for the development of antiviral drugs. In this study, we used a cell-free in vitro assay to examine biochemical characteristics of two rabbit calicivirus RdRps and the effects of three antivirals that were previously identified as norovirus RdRp inhibitors (i.e. NIC02, NIC10, NIC12). Our experiments revealed an unusually high temperature optimum (between 40-45°C) for rabbit calicivirus RdRps, which may reflect an adaptation to a host with a body temperature of more than 39°C. We also identified the non-nucleoside inhibitor NIC02 as a suitable scaffold for further drug development against rabbit caliciviruses: NIC02 exhibited inhibitory concentration 50 (IC50) values of 19.9 µM (95% CI: 9.1-57.0 µM) against the RHDV RdRp and 13.5 µM (95% CI: 10.9-29.0 µM) against the RdRp from a non-pathogenic rabbit calicivirus (RCV-A1). The results of this study will aid future drug development against rabbit caliciviruses.