by Paul Karr

Pacing the halls of his third-floor lab in the University of Georgia College of Pharmacy, Distinguished Research Professor Chung K. “David” Chu doesn’t carry the air of someone who designs the future. Yet Chu and his team of students literally are creating substances that have never been known to mankind: the drugs that might one day stymie some of the toughest viruses on earth, including hepatitis B and C viruses, HIV and smallpox virus, among others.

It may take five to 10 years of painstaking analysis for any one of these chemicals to prove successful — and there are far more failures than successes. But Chu and his research team are driven by the hope that just a few of these compounds might score a precise hit on an elusive target — that they might halt or even kill a virus without harming the human it has infected.

In the process, Chu draws countless complicated molecular structures in grease pencil on a board in his office, sending his graduate students and postdoctoral fellows energetically back to the lab to figure out how to make them.

“Drug discovery is a very risky venture and time-consuming business,” Chu said, “and patience is everything. If you’re not patient, if you don’t have that, then you’re out of the game. Yet you’re also striving to be the first in the world to discover something; there is no prize for second place in this race.”

Wrenches in the viral works
Born into a family-owned pharmaceutical company in South Korea, in 1968 Chu came to America, where he earned his graduate education. After a stint with the prestigious Memorial Sloan-Kettering Cancer Center in 1974, Chu began his academic career in Idaho, returning east to UGA in 1982.

Since then, he has worked on everything from male contraceptives to antidotes against bioterrorism. But his consuming research interest has always been hunting down new agents that might stop emerging infectious diseases and cancer in their tracks.

“This is why you get into the field of medicinal chemistry,” Chu said. “You want to help people; you want to ease suffering. It is a very tough job as an academician, but if you are successful, in my opinion, no other area of science could match the rewarding experience of medicinal chemistry.”

In particular, he has focused on a class of substances known as nucleoside reverse transcriptase inhibitors — “nukes,” for short, in the lingo of antiviral drug designers. These substances work by fooling a virus as it tries to recopy itself within human DNA.

A virus’s copying mechanism is rapid and ruthless, but it’s also “sloppy” in a biologist’s words; in its haste to multiply, it sometimes makes mistakes. Chu’s most effective drugs (see “Hits & Misses,” page 31) target a sneaky process known as reverse transcription, which enables some kinds of viruses — such as HIV — to infect the body. During the process, a viral enzyme called reverse transcriptase converts the virus’ single-strand RNA (ribonucleic acid) into double-helix strands of DNA; that DNA is then incorporated into the human chromosome, where it directs the infected host cells to rapidly copy viral RNA. A person infected with HIV soon will carry tens of thousands of copies of the virus in each drop of blood, a staggering quantity that eventually overwhelms the body’s immune system.

The right medicine can slow or stop the HIV infection process by mimicking the chemicals that reverse transcriptase needs to perform its disguise and then binding to that enzyme’s chain of infected DNA — essentially capping it off like a safety cover over an electrical outlet. Cocktails of two different kinds of these nukes, mixed with a third type of drug known as a protease inhibitor, are currently the most effective drugs at keeping HIV from worsening and eventually causing AIDS.

Still, none of the nukes can cure or even reverse the onset of AIDS, and their side effects can be devastatingly severe. Chu’s goal, then, is to find a drug that will attack the virus without also fooling healthy cells into an early death. In DAPD, he and collaborator Raymond Schinazi, a pediatrics professor at Emory University’s VA Medical Center, may have finally hit on one.

“It seems very promising, based on our pharmaceutical partner’s preliminary clinical studies,” Chu said.

If he sounds guarded, that’s because finding an effective new drug is extremely difficult. The UGA Drug Discovery Group — which consists of Chu and Doug Boudinot, associate dean of the Graduate School, plus a changing roster of about a dozen graduate students and postdoctoral fellows — has been remarkably productive synthesizing more than 1,000 compounds, some of which seem promising as antiviral agents. Chu personally holds or shares several dozen U.S. patents and has garnered millions of dollars in research grants and contracts from the National Institutes of Health and pharmaceutical firms during his 19 years at the university.

Yet even his most promising finds, drug discoveries with names like CS-87, have never made it to all the way the drugstore for one reason or another: poor test results, toxic side effects, even lack of interest by a pharmaceutical company.

“That’s all part of the frustration and the challenge as an academic investigator,” Chu said. “But that’s what keeps you going: the goal.”

Long road to approval
HIV is just one of the devastating diseases Chu seeks to destroy. He also has his sights set on an even more widespread killer: the hepatitis B virus.

Hepatitis B is most prevalent in Asia, Africa and, interestingly, northern Canada and Alaska (which may point to a common ancestry for these peoples with Asians). Some 2 billion people in the world — roughly a third of the Earth’s population — show signs of past or current infection, and 350 million of those, or one in 20 worldwide, exhibit a chronic infection; that figure includes more than one million people in the United States alone. One million of those infected worldwide die of it annually, many from the liver cancer or cirrhosis of the liver that it precedes.

Chu said a vaccine could possibly prevent 90 percent of the infections.

One very promising candidate, L-FMAU, could be approved for hepatitis as early as 2003. Typically, it takes seven to 10 years for a drug just to make it from conception to development to the clinical trial stage. That would represent a decade of work — and a major triumph — for one who has largely toiled in relative obscurity.

“He’s not at the cutting edge; he is the edge,” said Schinazi, who has worked with Chu for the past 15 years.

It’s Schinazi who receives the carefully packed containers of new compounds developed in Chu’s lab. The pediatrics professor quickly begins testing them in dishes of cell cultures to find out just how the compounds interact with viruses, how they are broken down by the healthy cell and what the potentially dangerous byproducts of those reactions might be — the first step down the long, long road to drug approval.

Others have taken notice of Chu’s lab, as well. Chu recently helped broker a deal between the University Georgia and Kyungsan University, a college of Eastern medicine located about 200 miles south of Seoul, South Korea. Together, they will research the potential antiviral properties of Korean plants.

“My life has been good, my work has been good, my research has been good,” Chu reflected. But he added that he feels something is still missing.

“I would like to have a drug approved,” he finished quietly. “That would really be something important, not just personally but also for the university and for society.”

For more information, access http://www.rx.uga.edu/main/home/chugroup/index.html.

Paul Karr is a prize-winning journalist and writing consultant who contributes regularly to Research Reporter.