Virus Replication Inhibitors

Viruses are intracellular parasites that need the host-cell machinery for replication. Inhibiting virus replication using miRNA or siRNA has been described for several viruses. Although miRNAs have been shown to augment hepatitis C virus replication, a number of other host miRNAs have been shown to inhibit replication of hepatitis B virus, influenza virus and vesicular stomatitis virus; a virus closely related to RABV. In addition, siRNA targeting viral sequences have been shown to inhibit in vitro replication of influenza virus and poliovirus. RABV replication has also been shown to be inhibited by siRNA in vitro.

One of the approaches to treatment of rabies that has had some success experimentally, but no robust clinical benefit after the onset of disease, is the use of immunoglobulins to neutralise virus in the CNS. This limited success has been in part, attributed to the intact BBB, as antibody secreting B cells within the CNS do have a clinical effect. Therefore a specific virus neutralising treatment that can cross the BBB would have great therapeutic potential. Aptamers are single-stranded nucleic acids that can fold into stable three-dimensional structure and bind specifically to various macromolecules, viruses, and cells. RNA aptamers are isolated from a large pool of nucleic acids by a robotic iterative selection process called Systematic Enrichment of Ligands via Exponential system (SELEX). Until recently applications of nucleic acid aptamers have been hampered by a range of patents encompassing the basic technology. These are now beginning to expire and the level of activity in the field is increasing sharply as a result. They have enormous potential as therapeutics due to their ability to directly block or interrupt the functions of target proteins with minimal or no harmful side-effects. The first aptamer therapeutic was FDA approved in 2005 and a number of clinical trials are currently underway for the use of aptamers in diseases such as neurological, neoplastic and vascular conditions. RNA aptamers against the major RABV glycoprotein are already available. Preliminary data has demonstrated that these are able to neutralise rabies virus in vitro.