With proof-of-principle in his pocket and a new $2.2 million grant from the National Institutes of Health (NIH), SLU scientist John Tavis, Ph.D., will take his 25 year mission to finally develop a cure for the hepatitis B virus into the next phase.
Tavis, who is professor of molecular microbiology and immunology at Saint Louis University, says his team has built a warhead that will kill the virus; now, it's time to design a cruise missile that will deliver the drug.
After exposure, the hepatitis B virus can linger, causing chronic infection in many people. Over time, the illness causes liver damage. While current treatments can suppress the virus, they cannot fully kill it, and it will return if treatments are stopped.
More than 350 million people are chronically infected with the hepatitis B virus. Of those infected, up to 1.2 million die from liver failure and liver cancer each year.
Because current treatments are costly, lifetime medications, scientists are keen to develop better options, likely in the form of combination therapies, to knock out the virus for good.
Tavis and his team have finished one stage of research and are moving on to another in their quest to design a new drug.
"We've achieved the first stage of the laboratory research. We've developed the warhead of a drug, the portion that does the actual activity that the drug is designed to do. We did this with a class of compounds called alpha hydroxyl tropolones.
"We have advanced beyond what is called 'target identification and validation'," Tavis said. "We found something to hit in the virus and proved that it is a good thing to hit. Then, we identified about 35 inhibitors. This tells us about the types of compounds needed to block the viral activity. This is the first step to drug development. Now, we're done with proof-of-principle part of the work.
"The inhibitors we found are the warhead of the drug, but this is only one portion of a drug. The next part is the delivery, which involves all kinds of things. We must design a molecule for minimal toxicity, that can be absorbed by the body and that can last long enough for therapeutic benefit. Then, we've got to package it so people can take it in a pill. Ideally, we'd like to avoid injectables, which are difficult for people to take.
"So, now we've got to design the package -- the cruise missile -- that will hold and deliver the warhead."
The recent NIH grant will allow Tavis, his key collaborators Ryan Murelli, Ph.D., of the City University of New York and Marvin Meyers, Ph.D., director of medicinal chemistry at SLU's Center for World Health and Medicine, and the rest of his team to take their promising findings a step closer toward drug development. This stage will focus on medicinal chemistry, testing the drug in repetitive cycles aimed at optimizing the drug and limiting toxicity.
"We need an inhibitor that is safe enough and good enough to give to people," Tavis said. "This is very hard work. While this new grant won't get us all the way there, if we are very successful we will get deep into the preclinical stage in preparation for clinical trials."
Tavis credits early support from the NIH and SLU, as well as the unique collaborations possible through partnership with SLU's Center for World Health and Medicine (CWHM) with allowing his work to progress.
"Drug design has not traditionally been done in academia," Tavis said. "The work is not always compatible with academic duties and it requires an interdisciplinary team. It can be difficult to organize the workflow. But, the Center for World Health and Medicine at SLU is a unique resource. It has enabled those of us in the basic sciences to advance our work."
Initial research funding for Tavis's work included seed grants that allowed him to gather enough data to publish early findings and attract NIH funding.
"This project is a result of 25 years of background studies in basic science funded by the NIH," he said. "And, the initial stages of the more recent work were generously supported by seed grants from SLU through the President's Research Fund. We also received funding from the "Friends of the Saint Louis University Liver Center" and from SLU Cancer Center, as well as Washington University's Institute of Clinical and Translational Sciences. All of those different organizations saw value in this work at an early stage, invested, and now we are seeing the payoff."
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