BTA-798 is being developed by Biota Pharmaceuticals Inc., whose corporate offices are in Atlanta, Georgia and their R&D facilities are in Melbourne, Australia, and Oxford, United Kingdom.
Biota is focused on the discovery and development of direct-acting antivirals to treat infections that have limited therapeutic options. Biota has vapendavir, an oral treatment for human rhinovirus infections in moderate-to-severe asthmatics.
Pleconaril was liscensed by ViroPharma, who sold it to Schering-Plough in 2003. They reformulated it into a intranasal spray. It reached phase II in clinical trials for the treatment of common cold symptoms and asthma complications, but the results have yet to be reported.
Pleconaril is also being studied for its efficacy in infants with enteroviral sepsis syndrome.
Viral RNA Replication Inhibitors
Viral RNA replication occurs later in the EV life cycle, and the following compounds have shown activity during these cycles.
A novel compound, TTP-8307, potently inhibits the replication of several enteroviruses, including coxsackievirus B3 and polioviruses by interfering with the synthesis of viral RNA
TTP-8307 was identified in a screening campaign as a selective inhibitor of CVB3 replication in Vero cells. The effect of TTP-8307 was also evident against coxsackieviruses A16 and A21, but not EV-71.
TTP-8307 inhibits human rhinoviruses (HRVs) 2, 29, 39, 45, 63 and 85, but not other rhinovirus serotypes (HRV serotypes 9, 14, 15, 41, 42, 70, 72, 86 and 89).
TTP-8307 inhibits viral RNA synthesis in a dose-dependent manner, without affecting polyprotein synthesis and/or processing.
The NIH Clinical Collection library consists of 446 highly drug-like compounds that have been tested in clinical trials for a large variety of indications. One of the small molecules was a hit for inhibiting Enteroviruses; Itraconazole.
Itraconazole is an antifungal agent that is also being explored as an anticancer agent, and it works against the RNA replication stage of EV.
Several lines of evidence suggested that the antiviral activity of Itraconazole involves OSBP and/or ORP4, both of which are sterol-binding proteins implicated in sensing and transfer of sterols at membrane contact-sites. Further investigation is required to determine the role for OSBP/ORP4 in enterovirus replication.
Proteins 2A and 3C are proteases of Enteroviruses and are important for viral replication. By blocking 3C viral protease, a protease inhibitor could possibly be combined with a capsid binding inhibitor to inhibit EV replication.
Other protease inhibitors, polymerase inhibitors, and 2C targeting compounds could also be used in a combination regimen for treating chronically infected EV patients.
Capsid Binding Inhibitors target the 4 structural proteins: VP1-4. But there are also 7 non-structural proteins that could also be targets for an antiviral.
All 7 non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C and 3D) possess different functions and are produced during co- and post-translational events.
Genetic studies have implicated a role of the non-structural protein 2C in the formation of poliovirus.
Compounds Targeting 2C
Targeting the viral polymerase can be an effective method for antiviral treatment. This can be illustrated by the fact that first-line HIV treatment currently consists of two polymerase inhibitors.
Polymerase inhibitors can be divided into nucleoside/ nucleotide analogues and non-nucleoside inhibitors (NNI). NNI's can have a variety of mechanisms of action, such as stabilizing the enzyme so that necessary conformational changes cannot take place.
GPC-N114 is a novel non-nucleoside inhibitor of RNA Polymerase. It is a small molecule that exerts its activity against EV at the RNA replication stage.
Coxsackievirus B-3 (CVB-3), had a high geneti barrier to resistance against GPC-N114. It acts by interfering with binding of the RNA template-primer and identifies a new pocket that can be used for the design of broad-spectrum inhibitors of EV replication.
GPC-N114 is the first polymerase inhibitor that binds the site of the template acceptor nucleotide. The identification and characterization of GPC-N114 is an important contribution to the field of antivirals for EV, identifying a pocket in the polymerase that can be targeted by Non-Nucleoside Inhibitors.
Other common targets for antiviral therapy are the viral proteases since these are essential for correct processing of the viral polyproteins.Protease 3C is the target for an EV compound.
In addition to their function in polyprotein processing, viral proteases target a variety of host proteins for efficient virus replication.
Protease inhibitors developed for HIV and hepatitis C virus, have demonstrated the suitability of these targets for antiviral therapy.
SG 85 inhibited Enterovirus 3C proteases.
AG 7088, AG 7404, and SG 85 are peptidomimetic active site inhibitors which have been designed based on the cleavage site recognized by the targeted protease.
RNA viruses cause diseases that can be very difficult to treat.
RNA viruses replicate their genomes with a very high error rate, giving rise to populations that contain a large genetic diversity.
RNA viruses possess a great adaptive capacity that permits them to rapidly generate drug‐resistant mutants, as well as antibody or cytotoxic T lymphocyte escape mutants.
One of the most successful strategies to control RNA viruses is the use of combination therapies
Other chronic RNA viral infections, such as HIV and HCV, are treated successfully with a combination of several drugs that work at different stages of the viral life cycle.
This regimen of combining antiviral drugs could be applied to patients infected with Enteroviruses, making recovery a reality.