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

Polyanionic macromolecular prodrugs of ribavirin : antiviral agents with a broad spectrum of activity (#145)

Tracey Hinton 1 , Kaja Zuwala 2 3 , Celine Deffrasnes 1 , Shawn Todd 1 , Shuning Shi 1 , Glen Marsh 1 , Megan Dearnley 1 , Benjamin Wohl 3 4 , Martin Tolstrup 2 , Alexander N Zelikin 3 4
  1. CSIRO, AAHL, Geelong, VIC, Australia
  2. Department of Infectious Diseases, Aarhus University Hospital, Aarhus , Denmark
  3. Department of Chemistry, Aarhus University, Aarhus, Denmark
  4. iNano Interdisciplinary Nanoscience Centre, Aarhus University, Aarhus, Denmark

Viral infections continue to constitute a tremendous socio economic burden in agricultural, veterinary, and healthcare sectors. The costs to contain viral epidemics are enormous. One of the major drawbacks of the current antiviral tools is the lack of broad-spectrum antiviral agents.
The aim of this study was to initiate the development of broad spectrum antiviral agents – specifically based on synthetic polymers developed by Reversible Addition Fragmentation Chain Transfer (RAFT) and macromolecular (pro)drugs of ribavirin (PAMP of RBV). In this formulation the polymer and drug can exert antiviral activity through three independent yet complementary mechanisms,
1. The polyanionic polymer can prevent viral cell entry through a non-specific association of the polymer with the viral particle
2. The polyanionic polymer may exert an intracellular antiviral effect by acting as a competitor to the viral nucleic acids for binding to the polymerase
3. The polymer carries Ribavirin via a cleavable linkage for release upon cell entry, thereby reducing Ribavirin toxicity
A pool of 13 polyanionic polymers, with or without RBV attached, was tested against eight representative viruses from five RNA virus families all important in human health including Influenza, Measles, RSV, HIV, HCV, Ebola, Dengue and Mumps. One particular PAMP of RBV formulation was active against 6 of the viruses. Interestingly this broad spectrum of activity manifested itself differently across viruses. Thus, for HIV and Ebola, it was the polymer that appeared to contribute the greatest to the overall effect – specifically through the inhibition of virus cell entry. For influenza and measles, it was the efficient delivery of the conjugated RBV that was active.
The lead formulation was also shown to be effective in a pre-in vivo model using chicken embryos whereby the formulation significantly suppressed infectivity of influenza virus. The data paves the way to the development of powerful new broad spectrum agents to alleviate the healthcare and socioeconomic burden of viral epidemics.