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How would you summarize your research?
LIU: Overall I would say that my laboratory tests small molecules to see if they react in our bodies to find potential drugs to treat disease. We are also looking for new targets in the body that may cause disease so we develop drugs against these. We then use chemistry to manipulate these small molecules to be better suited for their molecular target—meaning they bind better, are less toxic or are more potent. Contributing to this goal, we have created a drug library.
LIU: This library is not made of books, but is rather a collection of drugs. Most of the drugs in our library are FDA approved or have been proven in other countries for treating human diseases. It also includes drug candidates that have moved through phase I and have entered phase II clinical trials, meaning these drugs have been shown to be tolerable and relatively safe in humans. But, whether they are effective for the intended disease remains unknown. We focus on these compounds because they have cleared early approval hurdles and may be short-tracked to the clinic.
How is the drug library used?
LIU: We test the library to find new leads for different types of diseases. This library has become a free resource for all researchers here at Hopkins. At last count maybe close to 20 research groups at Hopkins have used our library.
We have identified a number of drugs that possibly could be used to treat a number of different diseases and some are being tested in clinical trials. What we are doing now is figuring out exactly how they work at the molecular level, because understanding the mechanisms of action of these drugs in a new disease context will facilitate the future design of treatment options.
Can you tell me about some of your successes from the drug library?
LIU: A specific example is an antifungal drug called itraconazole. It’s been used for treating both systemic and topical fungal infections. What we discovered was that it also inhibits new blood vessel growth by halting endothelial cell growth. We subsequently showed that it blocks new blood vessel growth in mice and consequently it slows down significantly tumor growth in mice with prostate and breast cancer. Two of our colleagues in the Johns Hopkins Kimmel Cancer Center now are testing this drug in two separate clinical trials against lung cancer and prostate cancer. Initial data looks very promising.
We’ve also looked for drugs that work against HIV, which brought us some very interesting hits—some are published already. And, we’ve looked for drugs that kill bacteria and malaria parasites. We had an earlier story about an antihistamine being useful in treating malaria.
How did you get involved with malaria research?
LIU: Curiosity got me into this line of research. Malaria affects millions worldwide, yet it’s not as well studied as cancer or diabetes. My clinical pharmacology colleague Theresa Shapiro, who works on finding drugs that treat malaria and other parasitic diseases, and I discussed a hunch we had about a substance called fumagillin that was known to have anti-parasite effects in honeybees. We thought it also might inhibit the activity of malarial parasites. We started testing this idea in the lab thanks in part to the generous support of the Johns Hopkins Malaria Research Institute.
Congratulations are also in order for your 2010 NIH Pioneer Award. How do you plan to use those funds?
LIU: Thank you. I have a totally new idea to design new types of molecules based on natural products. Many molecules in nature have a ring-like structure because these kinds of structures are stable. We will start with the ring structure and then add chains of protein building blocks. The library will contain hundreds of thousands or even millions of compounds with different combinations of these building blocks. Then we will test this new library to look for new proteins that these molecules may bind. We want to discover new small molecule inhibitors for proteins that currently do not have small molecule inhibitors. If we are lucky and the protein happens to be implicated in human disease, then we would have a lead for a potential drug.
What was your inspiration for studying molecular science?
LIU: I was an undergraduate chemistry major and then completed a master’s degree in organic chemistry. However, I was always fascinated by biology and decided to enter a biochemistry doctoral program at MIT. So I have been fortunate to be able to combine my interests in chemistry and biology. Interestingly, we published a paper most recently on the potential compound for treating malaria was published in the journal Chemistry & Biology and this really brought my scientific training full circle.
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