Potent, orally available, broad-spectrum antiviral agents are an unrealized goal of the medical community. Most antiviral therapies directly inhibit viruses, are not broad-spectrum and can lead to drug resistance. In light of the threat of novel emerging viruses (e.g. Pandemic-Influenza), existing medically important viral infections, and the challenges associated with rapid diagnosis of causative agents, treatment with currently available viral specific molecules are suboptimal.

Alios’ approach to developing such broad-spectrum antiviral agents has been to study interferon pathways. Interferons are induced in mammalian cells in response to viral infection and represent the first line of defense against these important pathogens. Interferons can be directly administered to patients to treat various viral infections, but they have a number of drawbacks including the need for injections and the non-specific nature of their effects leading to unwanted side effects. In order to retain interferon’s anti-viral effects without the associated side effects, Alios has focused its efforts at the end of one of the pathways that interferons activate, the RNase L system.

The 2’5’ oligoadenylate synthetase RNase L system is one of the principal ways in which interferon inhibits virus replication. RNase L is a latent endoribonuclease that is expressed in most cells. In order to activate RNase L, interferon-induced 2’-5’-oligoadenylate synthetases must first make an unusual nucleic acid molecule from ATP called 2-5A. This molecule consists of a series of 5’-triphosphorylated oligoadenylates with 2’-5’ phosphodiester bonds. Trimers and tetramers of 2-5A appear to have only one function, activation of RNase L. Initial binding of 2-5A to the Ankyrin domain of RNase L triggers a conformational change that induces the dimerization of the protein. Subsequently, the active RNase L dimer binds to and cleaves its single stranded RNA substrate at UU and UA residues. This last catalytic step, also called endonuclease activity, is directly responsible for the antiviral effect of the activated RNase L. Activation of RNase L is an ideal target for broad spectrum antiviral drugs since all viruses utilize RNA in their lifecycle. However, 2-5A has a number of pharmacological properties that make it a poor candidate for drug development.

To address these deficits, Alios is developing proprietary allosteric activators of RNase L based on structural modeling of the binding of 2-5 A to the activation site of RNase L. To date, in vitro testing has demonstrated that Alios RNase L activators exhibit broad spectrum anti-viral activity against a number of important viruses that cause serious diseases in humans. This broad spectrum of activity highlights the potential of these molecules to revolutionize the treatment of serious viral infections.