San Diego company's three-dimensional diagrams provide direction in battle again

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San Diego company's three-dimensional diagrams provide direction in

battle against disease

By Terri Somers

UNION-TRIBUNE STAFF WRITER

December 23, 2003

Few outside the laboratory paid attention recently when the San Diego

biotech Structural Genomix found a way to build a three-dimensional

diagram of the microscopic protein that, when mutated, causes cystic

fibrosis.

Few outside the laboratory paid attention recently when the San Diego

biotech Structural Genomix found a way to build a three-dimensional

diagram of the microscopic protein that, when mutated, causes cystic

fibrosis.

But to Suzanne Pattee, it was big news.

Pattee, a 40-year-old land woman, lives with the genetic

disorder, which encourages her body to suffocate her by constantly

filling her lungs with a thick mucus. She has already surpassed the

average life span of cystic fibrosis patients – 33.4 years – thanks

in large part to biotech drugs.

Now, she is hopeful that Structural Genomix's diagram could be used

to develop better treatments for the disease by showing scientists

where and how a drug's molecules should bind to the protein to

correct the mutation.

While that could take another five years or more, experts say the

diagraming of the protein is a huge leap ahead.

" I'm optimistic when I hear about advances like this. It helps in the

day to day to keep going, " said Pattee, a lawyer who works with the

Cystic Fibrosis Foundation. " Obviously I'd like it tomorrow. My goal

is to stay healthy enough to benefit if this does come to market in

five years. "

The technique Structural Genomix used is called X-ray

crystallography, a complicated process that allows scientists to see

the molecule in the finest detail, down to each individual atom.

The approach, a technology that could help illuminate the path to

myriad diseases, is also employed in San Diego by at least three

other companies: Vertex, Syrrx and Pfizer.

Earlier this year, privately owned Structural Genomix used the

technology to determine the crystallized structure of the protease in

the virus that causes SARS. It took the company a speedy eight weeks

to meet that challenge. It took about 18 months to determine the

structure of the protein linked to cystic fibrosis. In decades past

it could take a team of researchers much longer to complete the task

using the same science.

The diagrams of both proteins determined by Structural Genomix have

been posted to a public databank for use by other researchers.

In cystic fibrosis, as in many diseases, there is a protein that for

genetic reasons becomes mutated and misshapen. To treat the disease,

scientists must find a small molecule that can fit into the mutation

and correct it. Many scientists liken it to a key fitting into a

lock, or a hand fitting into a glove.

X-ray crystallography also allows scientists to look at how the small

molecule is binding with the mutated protein. This allows them to

find the best drug candidate, or to determine how to tweak a molecule

so that it becomes a better drug candidate.

The alternative is to blindly test small molecules on a protein and

determine what works best.

The downside is that often researchers cannot determine that a

molecule is not a good fit until a lot of time and money has been

invested and side-effects of the treatment start to become visible.

" It turns out that X-ray crystallography is the only way we can

routinely determine the exact structure of molecules, " said Arnie

Rhinegold, an expert in X-ray crystallography at the University of

California San Diego. " It's gone from something that is done

occasionally to something that is routine. "

Dave s was practicing the science when it was not so routine.

It used to take a team of researchers several months to determine the

structure of just one protein. Now, thanks to advances in computer

software and hardware that aid in data collection and analysis, it

takes just weeks to determine the structure of a complex molecule

such as a protein or enzyme, s said.

As a researcher at UCSD, s saw the commercial potential for X-

ray crystallography. He left the lab to become one of the founders of

Agouron Pharmaceuticals.

That San Diego-based biotech used X-ray crystallography to develop a

treatment for HIV. The drug, Viracept, is a protease inhibitor in

which a small molecule binds to a protein, known as a protease, to

keep it from replicating. Viracept became the biggest selling drug

for a biotech the year it hit the market.

Agouron has since been swallowed up by pharmaceutical giant Pfizer.

Pfizer set a goal this year for its La Jolla campus to deliver four

compounds that look promising as drugs, s said, and the labs

delivered five. All were developed using X-ray crystallography.

" Pfizer is a very bottom-line company, constantly analyzing processes

and where we are adding value to the drug development pipeline, "

s said. " The fact that a vast majority of our compounds have

been structure-based reflects the value of X-ray crystallography, " he

said.

The technology, however, is only one step in the drug development

process.

Equally important is how scientists use the information provided by X-

ray crystallography to find molecules that make good drug candidates,

or how to tweak these molecules so that they bind better with the

protein, s said.

Making a small molecule bind better means a patient could need a

lower dose of a drug. Lower dosage can mean fewer side effects.

To the nonscientist, this technology may seem deadly dull. But it

gives s goose bumps: it often enables him to see something

that no one has ever seen before.

" This is endlessly fascinating because you are actually seeing how

molecules are put together – the very stuff from which life is made.

I'm always fascinated to see the myriad ways Mother Nature can string

atoms together to make molecules in ways you'd never suspect. "

But is the science a viable basis for a business?

In 1999 to 2000, when the first draft of the human genome was being

completed, dozens of companies were founded on the promise that they

could decipher this genetic information, helping drug development

companies find better drug targets and compounds. The industry and

its investors thought these " tool " companies were hot.

But interest waned. Companies were not willing to pay enough to make

many of these biotechs sustainable. The business model proved more

problematic than that of drug development companies that could make

millions with one blockbuster drug, said McCamant, editor of the

Berkeley-based Medical Technology Stock Letter.

Don't call Structural Genomix a tool company, chief executive Tim

said. The company has its own drug development platform, he

said. In addition to quickly determining the structure of a molecule,

the company's platform allows it to identify the small molecules that

will bind closely to the larger molecules, said. And the

platform allows this to happen quickly, said, pointing to the

eight weeks it took to diagram the SARS-related protease.

The company has leveraged that platform into collaborations, like one

with the Cystic Fibrosis Foundation and a contract with Eli Lilly,

that brought in more than $16 million in revenue this year,

said. He's hoping that the publication of the cystic fibrosis and

SARS discoveries will lead to collaborations with discovery companies

impressed with the Structural Genomix platform and its speed.

While he would not reveal more of his company's financial details,

said that the revenue should cover a " good portion " of its

costs.

In general, the technology continues to evolve, offering an

increasingly detailed picture of the molecular world.

s predicted that within the next five years, researchers would

make inroads in the diagraming of protein molecules that live within

the walls of cells. These molecules, which currently are too

difficult to crystallize, are thought to be the origins of diseases

such as diabetes, obesity and high blood pressure.