ATLANTA—Georgia State University has received a five-year, $2.2 million grant from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases to develop combination therapies for respiratory syncytial virus, or RSV, and related respiratory viruses, which are top causes of infant hospitalization in the U.S.
Richard Plemper, professor in the Institute for Biomedical Sciences, is the principal investigator on the project.
Though RSV is a common respiratory infection—most people will be exposed by early childhood—there is no vaccine or effective treatment. Just one medication is approved to prevent severe illness in a subset of high-risk infants and children, including premature babies.
“The younger the patient population, the more challenging drug development is, because the margin of safety must be so high,” says Plemper. “Yet the clinical need is huge because the current treatment is very expensive and therefore only sparingly applied.”
Developing therapies for RSV or other RNA viruses is also tricky because the genome of these viruses can change very rapidly in response to environmental conditions. This makes it easy for the virus to develop resistance to drugs.
“RNA reproduction is more error-prone than copying DNA, meaning mutations are often introduced during replication,” Plemper says. “These errors are random, but if a mutation appears that happens to block the drug in any way, that genome will have a massive advantage and take over the population.”
Combination therapies, or treatments that use more than one medication, can reduce the likelihood that drug-resistant strains will emerge, making them essential for clinical success. Plemper has developed a pair of compounds that can interrupt the virus’s ability to replicate, and pharmacokinetic studies will determine whether the drug candidates are effective at treating the infection in mice, particularly when used in conjunction with one another.
Both compounds target the RNA-dependent RNA polymerase enzyme, which makes copies of the virus’s genetic template and is necessary for replication. Yet each targets the enzyme in a different way, meaning the medications could be used simultaneously.
One drug uses a modified version of substrates—the molecule upon which the enzyme acts—to essentially poison the polymerase. The substrate is only accepted by the viral polymerase, not the host, or human, polymerase, which reduces the risk of side effects.
A second drug binds to the polymerase and inhibits long-range activity, pressing a brake pedal on the enzyme.
“Now we want to know whether the drugs act synergistically—when we put them together, does it magnify the effectiveness?” Plemper says.
View an abstract of the grant, R01AI071002-12, at the NIH’s Project RePORTer website.
Institute for Biomedical Sciences
Plemper’s research is primarily focused on understanding how RNA viruses of the myxovirus families (influenza virus and human pathogens of the paramyxovirus family) enter cells and replicate their genetic information, and applying this insight to the development of novel antiviral therapeutic strategies.