Using technology to improve care

Hepatitis C Research Gets a Boost

A new computer-based technology, which enables better analysis of protein structures, has resulted in what could be the basis for better treatment of hepatitis.

Hepatitis C Research Gets a Boost
By Kristen Philipkoski

2:00 a.m. Jan. 9, 2002 PST

SAN FRANCISCO -- When researchers at Vertex Pharmaceuticals chose hepatitis C as the disease they hoped to treat, they didn't realize the uphill battle they faced. But thanks to new drug discovery technologies, they've come up with a drug that, if successful, will work much like many of the drugs effective against HIV.

Drug discovery is not easy. It often takes about 10 years and $5 million to $10 million to bring a drug to market. But there are some things that can make it harder than normal, such as a disease molecule that just doesn't want to stick to a drug.

In such cases, many companies give up. Vertex was tempted to, and would have had no choice a decade ago. But new computer-based technologies, especially protein structure analysis techniques, helped them build a potential drug to the exact specifications of the hepatitis C disease protein.

We knit together the biophysics, testing in the lab, the structural information and all of the processes. That's what we do best," Joshua Boger, the Vertex CEO, said.
Vertex announced the potential drug, a molecule called LY570310, also known as VX-950, on Tuesday at the J.P. Morgan H&Q Healthcare conference. The drug is at the point where they're ready to test it in animals, and soon after, humans.

Hepatitis C is an infectious disease of the liver that chronically affects approximately 2.7 million in the United States. It's nearly always fatal; kills slowly, often with no symptoms; and is usually caused by intravenous drug use.

The drug is a "hepatitis C protease inhibitor." If that sounds familiar, it's because the breakthrough drugs for treating AIDS are also protease inhibitors. Protease inhibitors prevent a virus from creating infectious copies of itself.

But unfortunately for Vertex researchers, that's where the similarity ends.

The HIV protease molecule is physically attractive to drug designers. It has what looks like a big tunnel going through it, and researchers were able to design a drug that neatly stuck inside.

Vertex researchers figured out exactly what the hepatitis C protease protein looks like down to the last atom in 1996, but its three-dimensional structure was a bit disconcerting.

They found its surface was practically smooth, with no big valleys or holes to stick a drug into. Instead they saw nothing more than a slight indentation.

"There was kind of a little dimple on the surface," Boger said.

Researchers have enough trouble making chemical compounds, that will dock onto a protein to counteract a disease when there is a clear place to put it. One with no "docking station" poses an even bigger problem.

Vertex has one drug already on the market for HIV, also a protease inhibitor called Agenerase, which received FDA approval in 1999. Finding the chemical compound that eventually became Agenerase was easy compared to the hepatitis C drug, Boger said.
To find their hepatitis C molecule, Vertex researchers used X-ray crystallography to analyze the finest details of that little dimple.

Eli Lilly signed on as a partner to find a drug candidate, initially investing $5 million.

Researchers tried the entire library of Lilly's chemical compounds against the hepatitis C protein, to no avail.

Pummeling a disease protein with as many chemical compounds as are available is the old, inefficient method of discovering drugs. Now, researchers have found ways to guide discovery by analyzing the physical structure of the proteins.

"The structural information was absolutely essential," Boger said.

Scientists had to create a chemical compound with every atom positioned in exactly the right spot to fit on the dimple.

Researchers may be able to do two physical tests in the lab per day, but in the same time they can perform millions of computer simulations. They combined both to guide their development of a precisely designed potential drug.

Now that they've identified the hepatitis protease inhibitor, tests in animals and eventually humans (Vertex hopes), will tell whether their efforts will result in a marketable product

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