Virus researcher aims at new target

All scientists latch onto a system to study. Some examine fruit flies. Others look at mice. Robert Ricciardi, chair and professor in the Department of Microbiology in Penn’s Dental School, studies viruses.

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Ricciardi, who has been at Penn Dental since 1992, began studying viruses early in his career because he has long been interested in the process of gene expression, or how genes are controlled and regulated.

“Viruses are great systems to study gene expression because you can manipulate them,” he says. “Many of the rules that apply to the control of gene expression in viral genes also apply to human genes, so you get that double effect.”

In gene expression, scientists can understand how a virus works, especially with important infectious diseases, and also begin to realize the common threads that occur throughout nature.

As a post-doc at Harvard Medical School, Ricciardi says he became involved in one of the first mapping technologies in the very early days of genome mapping. One groundbreaking discovery from that research involved NF-kappa B, a master regulator of the immune system that attaches to DNA through chemical modification.

For the past several years, Ricciardi and his team have focused on translational work that builds upon these earlier discoveries. He is working to discover therapeutics, or drugs, that can be used to control infectious viral diseases. In their experiments, Ricciardi’s team landed upon a protein known as the processivity factor, which is essential for the replication of viruses.

That was, Ricciardi says, his “lightbulb” moment.

“[The processivity factor is] a brand-new target. It’s a specific target, and when you hit it, you’re hitting something that’s absolutely [crucial] to DNA synthesis,” explains Ricciardi, who recently served as chair of the Microbiology Virology Parasitology Program, part of the Cell and Molecular Biology Graduate Group. “Without DNA synthesis, a virus cannot divide. It’s over. It’s a great way to destroy an infectious disease.”

Processivity factors, he stresses, are essential for DNA synthesis. They act like a tether in DNA, binding the helix to the polymerase, which is how DNA replicates and makes new strands. Without a processivity factor, the polymerase would separate from the helix and replication would not occur.

Processivity factors are found throughout nature—in everything from humans to E. coli—but they are different in every living thing. This means that a drug that targets the processivity factor in a virus won’t necessarily adversely affect a person. If a human’s factor is targeted, however, this would disrupt DNA replication and be toxic to a person’s system.

Ricciardi’s lab discovered processivity factors in four viruses: human herpes virus-6; Kaposi’s sarcoma; molluscum contagiosum; and smallpox. Ricciardi was awarded a grant from the National Institutes of Health (NIH) to find a drug that could work against smallpox, which is classified by the Centers for Disease Control and Prevention as a “Class A” bioterrorist threat. While a vaccine against this disease exists, Ricciardi notes that the vaccination could not be distributed fast enough for it to be effective in the event of an attack. 

Recently, Ricciardi also invented a test to rapidly screen for processivity factors, receiving a U.S. patent for his efforts. The procedure enables researchers to more efficiently screen chemical compounds that block DNA synthesis.

He is also using computer modeling to find the “sweet spot,” or precise locations in processivity factors, where chemical compounds prefer to bond.

Ricciardi notes that viral mutations, which occur often, can render drugs ineffective.

“[Mutations happen] all the time and this has been the dilemma early on with HIV. The first drug was AZT. It was a winner when it came out, people were so excited, and then it stopped working because there were viruses that acquired resistance to AZT,” Ricciardi says. “Now what you do is make a cocktail.” In this way, several drugs can join together to trick the virus and reduce the probability of it replicating. The idea of a cocktail of drugs that can target smallpox, he says, is of interest to the NIH.

“My wish is our smallpox therapeutic will be part of the cocktail for the other [smallpox antiviral drug] called ST246, and together they will work,” he says. “The whole idea, honestly, is to come up with something in case there is an attack that will really save millions of lives and devastation.”

Originally published on April 12, 2012