Drugs that operate on the targets of viral infection, rather than on viruses themselves, could provide an effective alternative for protecting against smallpox and other nasty pathogens.

Most of the therapeutic strategies currently developed to combat viruses target the particles themselves and focus on specific viral antigens or virus-specific enzymes. Ellis Reinherz of the Dana-Farber Cancer Institute (Boston, MA) saw potential in a different approach, which is directed toward cellular targets specifically involved in the process of viral infection. In the February issue of the Journal of Clinical Investigation, he and his colleagues present the outcome of one such investigation, an effort to develop new drugs to thwart poxvirus.

Facilitating the process of poxvirus pathogenesis are virus-specific growth factors that bind receptors on the surface of the host cell; for the smallpox growth factor (SPGF), this receptor is ErbB-1. Reinherz and his colleagues reasoned that this receptor might, therefore, make a viable target for blocking smallpox infection and thus began work on identifying drugs that can act on this receptor.

One of the compounds they identified, CI-1033, binds irreversibly and with high affinity to ErbB-1, and, although SPGF normally triggers a cascade of protein phosphorylation in cells expressing this receptor, treatment with CI-1033 decreases this signaling substantially. They also discovered that this compound reduced the size of plaques that formed in cell cultures infected with poxvirus, and data from these experiments suggested that CI-1033 was somehow blocking the release of mature virus particles from infected cells.

Reinherz's group continued their research with in vivo studies, using a variola-related poxvirus, vaccinia WR. Treatment with CI-1033 shortly before infection led to a marked improvement in the survival curve for intranasally infected mice, and the animals showed a significant decrease in the severity of their symptoms. There was even greater improvement in viral titer reduction and overall survival when CI-1033 was combined with a previously developed therapeutic antibody, anti-L1R, which targets a vaccinia-specific protein.

A final series of experiments tested the capacity of these therapies to protect mice after exposure—a scenario relevant to the perceived threat of smallpox as a potential bioweapon. After exposure to high doses of vaccinia for 2 days, mice then received various treatments; the antibody treatment contributed more substantially to overall survival, but the two treatments in combination led to significantly greater reduction in viral plaque-forming units and a general improvement in the animals' clinical condition. The inclusion of CI-1033 also led to a threefold augmentation of immune response in comparison with animals receiving anti-L1R alone.

These results, though preliminary, suggest an interesting new paradigm for drug design, one that could potentially bypass some of the limitations of pathogen-targeted treatments—such as the emergence of drug resistance—and provide a useful complement for existing pharmaceuticals.