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V-073, an enterovirus capsid inhibitor, was evaluated for its spectrum of antipoliovirus activity. V-073 inhibited all 45 polioviruses tested in a virus-induced cytopathic effect protection assay, with 50% effective concentration (EC50) values ranging from 0.003 to 0.126 μM. Ninety percent of the polioviruses tested were inhibited at EC50s of ≤0.076 μM (MIC90 = 32 ng/ml). V-073 is a promising antiviral candidate for the posteradication management of poliovirus incidents.
The World Health Organization (WHO), Rotary International, the U.S. Centers for Disease Control and Prevention (CDC), and the United Nations International Children's Emergency Fund launched the Global Polio Eradication Initiative in 1988. The initiative is approaching its goal and expects the world to be certified polio free in the near future. Protecting the 25-year and more than $7 billion investment in polio eradication will depend on the policies, tools, and tactics available during the final stages of eradication and in the posteradication era. The global public health community must be equipped to protect against virus reintroduction and, in the event of reintroduction, to rapidly contain, control, and eliminate the virus.
In November 2005, the National Research Council of the (U.S.) National Academies considered the potential role for antipoliovirus drugs in the eradication and posteradication management of poliovirus incidents. Currently, there are no antiviral drugs approved for treatment of poliovirus. The National Research Council concluded that there is indeed an important role for antivirals and recommended their immediate development (3). The case for developing antiviral drugs against poliovirus has been reviewed recently (2).
V-073 (Fig. (Fig.1),1), previously designated SCH 48973 (1), is a member of the picornavirus antiviral mechanistic class called capsid inhibitors. Antiviral compounds in this class inhibit picornaviruses by a virus-specific mode of action. These compounds integrate into the viral capsid at a specific site. Upon doing so, they prevent virus “uncoating” and the release of the viral RNA from the capsid, thereby blocking the initiation of the viral infection cycle (4). Other notable members of this class are pleconaril, disoxaril, and pirodavir. Unfortunately, these latter compounds lack the necessary antiviral potency and spectrum across poliovirus serotypes (2).
V-073 was previously reported to have broad-spectrum antienterovirus activity, including activity against poliovirus type 2, both in cell culture and in a poliovirus challenge model with mice (1). However, since the compound was then being developed for nonpolio enterovirus indications, its spectrum of antipoliovirus activity was not explored. Here, we present virus susceptibility data that indicate V-073 has specific, potent, and broad-spectrum antipoliovirus activity. Together with its other pharmacological attributes (to be reported elsewhere), V-073 represents a promising poliovirus antiviral drug candidate.
To assess the spectrum of antipoliovirus activity of V-073, a panel of 45 polioviruses was assembled and evaluated in a cell culture cytopathic effect assay. The panel consisted of viruses from all three poliovirus serotypes and included wild reference strains (poliovirus type 1 [PV1]-Brunhilde, PV1-Mahoney, PV2-Lansing, PV2-MEF-1, PV2-P712, PV3-Leon, and PV3-Saukett), the three Sabin vaccine strains, and representative circulating vaccine-derived poliovirus (cVDPV) isolates (12 PV1-cVDPV and 9 PV2-cVDPV) and vaccine-derived polioviruses from immunodeficient chronic excretors (iVDPV; eight PV1-iVDPV, four PV2-iVDPV, two PV3-iVDPV) collected from numerous geographic regions of the world over a period of time between 1981 and 2007. PV1-LSc/2ab, PV2-P712, and PV3-Leon are the parental strains from which the Sabin oral vaccine strains were derived, while PV1-Mahoney, PV2-MEF-1, and PV3-Saukett are the strains used to produce the inactivated polio vaccine. The assay for drug susceptibility measured protection by the drug of an LLC-MK2 cell monolayer from the virus replication-induced cytopathic effect and has been previously described (6).
The 50% effective concentration (EC50) values for the 45 individual viruses, as determined from seven-point concentration curves using a four-parameter curve-fitting program (SoftMax Pro; Molecular Devices), are provided in Table Table1.1. V-073 was active against all viruses in this panel, with EC50s ranging from 0.003 μM to 0.126 μM. The distribution of drug susceptibilities among these 45 polioviruses is depicted in Fig. Fig.2.2. Ninety percent of all polioviruses tested were inhibited by V-073 at EC50s of ≤0.076 μM (MIC90 = 76 nM; 32 ng/ml). In Table Table2,2, the mean EC50s for the various categories of polioviruses are provided. There appears to be no bias in the activity of V-073 among these virus groupings.
The selectivity index obtained for V-073 was 75, as calculated from a 50% cytotoxic concentration value for V-073 of approximately 6 μM [as determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay (5) after 72 h of exposure (data not shown)] and the MIC90 value. An earlier reported 50% cytotoxic concentration value of >50 μg/ml (>118 μM) was based on 18 to 24 h of exposure (1).
Testing the compound against a variety of viruses, as well as bacteria and fungi, revealed the specificity of V-073. Among the human picornaviruses, V-073 is modestly active against some nonpolio enteroviruses and poorly active or inactive against rhinoviruses and hepatitis A virus (1). Table Table33 summarizes drug susceptibility data for members of the Enterovirus genus, including the 45 poliovirus isolates, and a sampling of echoviruses, coxsackieviruses, and other enteroviruses. It is clear that V-073 is most potent against polioviruses and is substantially less active against the other enteroviruses.
V-073 had no activity against nonpicornaviruses, including adenovirus type 5, herpes simplex virus types 1 and 2, human immunodeficiency virus type 1, influenza A virus, measles virus, Punta Toro virus, respiratory syncytial virus, rotavirus 1, Semliki Forest virus, simian virus 40, and vaccinia virus (1). Finally, V-073 has no activity against a battery of gram-negative and gram-positive bacterial strains or fungus strains (data not shown).
Based on these in vitro antiviral results, the efficacy of V-073 in a mouse poliovirus challenge model (1), and the pharmacological attributes of the compound (our unpublished data), further development of V-073 is warranted. V-073 and compounds like it represent new tools that may play important roles in the posteradication management of poliovirus incidents. Such antiviral drugs could be used alone or as adjuncts to inactivated virus vaccines and may represent a key weapon in defending a polio-free world.
We thank the Task Force for Global Health, in particular Walter Dowdle, and the WHO for support. D.C.P. is a consultant to ViroDefense Inc.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Published ahead of print on 27 July 2009.