Penn Vet researcher makes progress toward controlling viral diseases

The Ebola outbreak in West Africa has claimed more than 140 lives in recent months. The disease is a frightening one, with fatality rates that can approach 90 percent and no effective vaccine or cure.

A pair of recent studies by the School of Veterinary Medicine’s Ronald Harty, an associate professor of microbiology, offer hope that Ebola and other viral diseases, including HIV and rabies, may one day be treatable by broad-spectrum antiviral drugs.

Viruses, which cannot reproduce on their own, hijack their host’s cells in order to replicate. After doing so, many viruses exit the cell in a process called “budding” in order to infect other cells and spread. In the two new papers, Harty and colleagues zeroed in on this step in the infection process, attempting to block it to reduce the infection to a level a person’s immune system would be able to control more easily.

Ebola

Ebola virus disease outbreaks occur primarily in remote villages in Central and West Africa, near tropical rainforests.

Looking for drugs that target interactions between a virus and host reduces the likelihood that a virus would mutate to develop resistance, Harty says.

“If they did that, the virus would be compromising its own ability to exit the cell and continue spreading infection,” he notes.

In the first paper, the researchers examined the interaction between the viral protein sequence known as PTAP, which is present in proteins that play important roles in the budding of Ebola and HIV, and the human protein Tsg101. This interplay is important for the virus to break free of the host cell’s plasma membrane and continue infecting other cells. Harty’s team screened various small molecules to find some that would block the interaction between PTAP and Tsg101, and found a promising candidate called compound 0013.

Testing the effectiveness of this molecule, they found that it reduced the ability of the virus to bud off from human cells in culture by more than 90 percent, and was similarly effective against proteins that are found in Ebola and HIV.

The second paper used an analogous strategy to try to block another viral-host interaction, this time examining the viral protein sequence called PPxY, which is found in the Marburg virus, the Ebola virus, the rabies virus, and a host of other dangerous pathogens. PPxY interacts with an enzyme in human cells called Nedd4 during budding.

Again, after screening many small molecules to see which would best inhibit the PPxY-Nedd4 interaction, the team found two strong candidate molecules. Further testing showed that they could effectively inhibit budding from occurring in models replicating rabies, the Marburg virus, and other infections, likely reducing the probability of an infection getting out of control.

Though Harty generally considers himself a basic scientist, he is excited about the potential clinical relevance of these early findings.

“The translational aspect is what makes this work so rewarding,” he says.

Originally published on April 24, 2014