ReviewA case for developing antiviral drugs against polio
Section snippets
Polio eradication
The Global Polio Eradication Initiative (GPEI), a partnership led by the World Health Organization (WHO), Rotary International, the US Centers for Disease Control and Prevention (CDC) and the United Nations International Children's Emergency Fund (UNICEF), is the largest, most expensive international public health project ever undertaken. Most would agree that the GPEI has been quite successful. When the program was launched in 1988, endemic wild poliovirus transmission occurred in more than
Current armament is not enough—new weapons needed
Developing strategies to respond to and control poliovirus outbreaks during the final stages of eradication and in a post-eradication era present significant challenges. First, there is the unpredictability of outbreaks. As VDPVs continue to circulate, there will be a high probability of outbreaks of paralytic disease in the first several years after OPV cessation, but their incidence and magnitude are unknown. Second, threats of accidental or deliberate release of wild type polioviruses and
Antiviral drugs and outbreak control
The idea of antiviral therapy for polio is not new. In the 1950s, shortly after the success of poliovirus propagation in cell culture, several inhibitors of in vitro polio replication were identified, some of which were evaluated in animals (Brown, 1952, Brown et al., 1953, Cochran et al., 1954, Francis et al., 1954, Knox et al., 1957, Barrbera-Oro and Melnick, 1961). In the 1960s, Hans Eggers was a vocal advocate of the concept of antiviral therapy for polio (Field and DeClercq, 2004).
How might a polio drug be used?
Currently, no poliovirus antiviral drug is available. However, if there were one, how might we use it? The above-listed general attributes of antiviral drugs portend multiple applications of a poliovirus drug in outbreak control both pre-eradication and post-eradication. Below, we discuss several possible situations in which an anti-polio drug might be used, including treatment, post-exposure prophylactic and prophylactic applications.
Development of polio antiviral drugs: excellent starting points
The technological feasibility of developing poliovirus drugs and the probability of clinical success have been clearly established by over three decades of drug development targeting the related rhinoviruses and NPEVs. These latter picornaviruses cause significant, widespread human disease for which there are no vaccines. Illnesses caused by rhinoviruses and NPEVs represented potentially lucrative commercial markets, and consequently have the attention of pharmaceutical companies.
True
Drug resistance
Development of resistance is to be anticipated for any antiviral drug that specifically targets a viral protein. Virus populations exist as quasispecies. Drug resistance is observed upon use of the drug on an otherwise drug susceptible virus population, during which minor pre-existing virus variants less susceptible to the drug are allowed to emerge as drug susceptible viruses are eliminated. In the case of positive strand RNA viruses, the error frequency giving rise to these variants in a
Development of polio antiviral drugs: who, how long and how much?
As outlined above, there are several strong starting points for development of anti-poliovirus drugs. Compounds that already show some anti-poliovirus activity could serve as scaffolds for the development of more potent and selective inhibitors when entered into a poliovirus-specific optimization program. While research programs should be initiated, there are also late stage preclinical and early stage clinical drug candidates specific for poliovirus that should be advanced (e.g., V-073 and
Closing comments
Polio eradication is within sight, but, like smallpox, the threat of polio will never go away. Protecting the estimated $7.3 billion, two-decade investment, and maintaining a polio-free world post-eradication, will depend on policies, defense strategies and emergency response capabilities available at the time of global eradication. These safeguards must defend against an accidental or deliberate re-introduction of the virus, and in the event of re-introduction, must be able to rapidly contain,
Conflict of interest statements
MSC is a principal in ViroDefense Inc. ViroDefense Inc, has been awarded a contract from the Task Force for Childhood Development and Survival to evaluate poliovirus antiviral candidate V-073, and is further participating in an NIAID program for provision of certain preclinical services. JN and JFM have no conflicts.
Acknowledgements
The authors wish to thank Walter Dowdle, Ellie Ehrenfeld, Sam Katz, and Dan Pevear, and others for their review of this manuscript, and their comments and suggestions.
References (76)
- et al.
Studies of rhinovirus resistant to an antiviral chalcone
Antiviral Res.
(1987) - et al.
2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder
Bioorg. Med. Chem. Lett.
(2005) Picornavirus inhibitors
Pharmacol. Ther.
(1994)- et al.
Antipicornavirus activity of SCH 47802 and analogs: in vitro and in vivo studies
Antiviral Res.
(1996) Antiviral agents against picornaviruses
Antiviral Res. Suppl.
(1985)- et al.
Involvement of membrane traffic in the replication of poliovirus genomes: effects of brefeldin A
Virology
(1992) - et al.
Basis for natural phenotypic resistance of human rhinoviruses to pleconaril
Antiviral Res.
(2005) - et al.
Failure to clear persistent vaccine-derived neurovirulent poliovirus infection in an immunodeficient man
Lancet
(2004) Vaccine-derived poliovirus from long term excretors and the end game of polio eradication
Biologicals.
(2006)Rhinovirus chemotherapy
Antiviral Res.
(2006)