Two grants from the National Institutes of Health will allow Saint Louis University researchers to build on breakthroughs in understanding the hepatitis B virus and begin the search for a drug to cure - not just halt - the illness.
Last year, John Tavis, Ph.D., professor of molecular microbiology and immunology at SLU published research demonstrating a way to measure and then block a previously unstudied enzyme, RNAseH, to stop the virus from replicating.
Armed with that knowledge, Tavis now has the early data and funding to begin the search for a drug that may help to cure patients with hepatitis B.
Current hepatitis B drugs can treat but not cure the infection for most people. Because the majority of liver cancer cases worldwide are caused by hepatitis B virus, a cure would dramatically cut liver cancer rates.
The assay Tavis found in last year's research is the measuring tool that allows researchers to gage the RNAseH enzyme's activity. It is how they will be able to tell if a drug will block the enzyme's function, and therefore stop the virus. However, until they perfect this measuring tool, they cannot efficiently look for drug candidates to eliminate the hepatitis B virus.
Tavis describes the next stage of the research process as an engineering problem.
"We must re-engineer the assay to be faster and of a better quality," Tavis says.
There are two problems researchers must resolve in order to move forward.
"First, the current assay is too slow," Tavis said. "It runs on a gel, which is good for studying how things work, but it isn't fast enough to look for new drugs. So, we'll convert it from a gel-based radioactive assay to a faster and easier florescent format.
"Next, the enzyme is currently at low concentration and not pure enough. So, we'll make the protein better, in terms of quantity and purity."
Once researchers have completed meticulous optimizing of both the enzyme and the assay, they will be ready for a small pilot test to screen drug candidates from known drug libraries.
At this point, they will hand the work over to robots, which will screen tens of thousands of potential drug candidates.
"To get the assay ready for the robots, we have to know how we're going to interpret what we find, to know how to detect what is a hit. That's what this process is about."
Additional work funded from a second grant will involve screening for active enzyme from as many hepatitis B virus genotypes as possible. There are eight known genotypes of the hepatitis B virus, each further apart genetically than a person is from a mouse.
Researchers will aim to find drug candidates that work for as many of the virus's genotypes as possible.
Tavis will partner with Marvin Meyers, Ph.D. director of medicinal chemistry at SLU's Center for World Health and Medicine (CWHM) and David Griggs, Ph.D., director of biology at the CWHM.
The CWHM is dedicated to the development of medicines to treat diseases that affect the world's poor and underserved populations. The center consists of a multidisciplinary team of former pharmaceutical company scientists with extensive translational research experience. They have the skills to discover and develop small molecule drugs, and they are experienced in advancing such agents into clinical trials.
Initial research funding for Tavis's work included grants from SLU's President's Research Fund, the SLU Cancer Center, and the Friends of the Saint Louis University Liver Center which allowed him to gather enough data to publish initial findings and attract NIH funding.
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