Broad-spectrum antibacterials have been around for so long that they are losing their effectiveness. But broad-spectrum antivirals have proved a harder cherry to pick.
The reason is that viruses lack their own replication machinery, sponging instead off their unwilling hosts to get their proteins made and assembled. So while it is possible to develop broad-spectrum antibiotics that interfere with the bacterial replication machinery, "most of the antiviral agents that have been developed target specific viral proteins," Robert Silverman told BioWorld Today.
Indeed, he said, the way to develop a broad-spectrum antiviral is to ignore the virus itself and instead give a helping hand to the host immune system.
Silverman is professor of cancer biology at the Lerner Research Institute in Cleveland, and senior author of a paper in the June 5, 2007, issue of the Proceedings of the National Academy of Sciences. He and researchers from the Cleveland Clinic, Cleveland State University and Japan's Gunma University report on compounds that have broad-spectrum activity against RNA viruses, which make up at least two-thirds of all viruses, including such pathogens as influenza viruses, HIV and the SARS coronavirus.
The researchers targeted RNase L, an enzyme that normally is present but inactive in "most if not all human cells," Silverman said, and activated only during viral infections. In the innate immunity cascade, RNase L is downstream of interferons, which are the linchpins of the innate immune response and also one of the few broad-spectrum antivirals around. Silverman said that downstream location should prove to be an advantage in any therapeutic applications, since while most viruses have evolved defensive mechanisms against interferons, the viral mechanisms by and large target the early stages of the interferon response.
Using high-throughput screening, the research team identified seven compounds that activated RNAse L in cell culture; the two most active ones were characterized more thoroughly. Silverman and his team showed that the two RNAse activators were able to inhibit the growth of five different types of RNA viruses. When control cells from RNase L knockout mice were treated with the compounds, they had no effect on viral growth.
The types of virus stopped in their tracks by RNase L activators included a retrovirus, and both single-and double stranded RNA viruses. Silverman said that breadth makes RNAse L a "bona fide target" with broad-spectrum activity against RNA viruses.
Silverman said that his team has "only just begun" animal studies to determine whether the compounds have in vivo activity. They are also trying to identify stronger activators, both by chemically modifying the ones they have and through further high-throughput screening. For now, the drugs may be broadly effective, but they are fairly weak: the effective concentrations were 100,000 times higher than that of the natural ligand that binds the same site.
Silverman is optimistic that such stronger compounds will not necessarily lead to toxicity problems, because the cell has an advantage over the virus in terms of RNase activity. "A viral genome only has to be cut once" to inactivate it, he said, while "the cell can always produce some more RNA if its supplies are cut up by an activated RNase. So we're working in this very large window."