Wall Street Journal - May 13, 2003
Mark Schoofs, Staff Reporter of The Wall Street Journal

Dr. Zhang brought the just-completed genome of the SARS virus to Dr. Ho and pointed out a hauntingly familiar DNA sequence. It was similar to one they had seen on the AIDS virus, where it codes for a protein that helps HIV infect human cells.

Even better, a drug exists that targets that protein and so stops HIV from infecting cells. Drs. Ho and Zhang believed they could design compounds -- called peptides -- to work in the same way against the SARS virus. And they did.

This past weekend, after a month-long scientific sprint involving work in New York, California and Hong Kong, the researchers declared that, in the test tube, the compounds blocked the SARS virus from infecting cells.

Whether this will develop into a usable treatment against severe acute respiratory syndrome won't be known until many more tests are conducted.

But the process of studying the genome and comparing it with other viruses -- as teams of other scientists around the world are doing as well -- is likely how a treatment for SARS will be found.

While Dr. Ho and his collaborators stress that it is a long road from promising laboratory results to a workable drug, and while the research hasn't yet been peer-reviewed, he is already pursuing the next step.

Tuesday, Dr. Ho is meeting with researchers from the Chinese Academy of Medical Sciences to design experiments involving animals. Even if the peptides never end up as actual medicine, the tale of how they came this far this fast is a parable of scientific creativity and drive.

"It was quite exciting to see a couple of [the peptides] work exactly as predicted," said Dr. Malik Peiris, who heads the SARS team at the University of Hong Kong and collaborated on the research with Dr. Ho.

"It's an indication of how quickly events are moving in terms of finding the virus, finding the genetic sequence and progressing from there to get to selective targets in the virus that can be inhibited, to block virus replication."

Robert Webster, the renowned influenza researcher at St. Jude Children's Research Hospital in Memphis, Tenn., called the work "a significant step" by "two of the best in the business," referring to Drs. Ho and Peiris. Dr. Webster, who wasn't involved in the research but heard about it at a meeting in Hong Kong with Drs. Ho and Peiris last month, added, "If they're getting some hits so quickly, that's proof of the pudding."

The peptides that Dr. Ho developed work by blocking the SARS virus from fusing to human cells, one of the first steps in infection. Peptides are synthetic proteins, made of amino acids. Roche Holding AG's drug Fuzeon is a peptide that works against HIV, the virus on which Dr. Ho made his name.

In early April, Dr. Ho, who says he had been watching SARS avidly, was invited by Hong Kong Chief Executive Tung Chee Hwa to consult on the SARS virus. The two men have known each other for years and Hong Kong is helping to build a lab for Dr. Ho to do work on an HIV vaccine. Doctor Ho made plans to visit Hong Kong in late April.

On April 13, about a week after his invitation from Mr. Tung but before going to Hong Kong, Dr. Ho was driving to work in New York when he heard on the radio that the genetic sequence to the SARS virus was posted on the Web. He and Dr. Zhang, a staff researcher at the Aaron Diamond AIDS Research Center in New York, which Dr. Ho runs, scrambled to get a copy of the sequence.

Just five hours after they got it, recalls Dr. Zhang, he came to Dr. Ho and said, "This is where we can contribute."

The speed of their discovery didn't just happen by luck. For years, Dr. Ho's lab has been studying the envelope of HIV -- the outer sheath of the virus that attaches to cells. Once SARS hit, Dr. Ho had also been reading up on coronaviruses, of which SARS is one. Indeed, Dr. Ho and Dr. Zhang were looking for something very special on the envelope of the SARS virus -- a coiled structure that pulls the cell membrane and the virus membrane together so that they can fuse.

Specifically, they were looking for a "heptad repeat," which is a repetition in the amino-acid sequence that occurs every seven amino acids and gives the protein its coil structure. That telltale repeat is present in HIV and other viruses. "It was certainly very nice to see" the heptad repeats, says Dr. Ho. Indeed, then he knew he could design peptides to interfere with the protein, because that is how the HIV drug Fuzeon works.

Essentially, fusion inhibitors are decoys that look very similar to part of the virus itself. In order for the SARS virus to fuse with the cell, the virus undergoes a complex process in which one part of its envelope, called HR1, interacts with another part, called HR2. The decoy peptides that Dr. Ho developed bind to either HR1 or HR2, stopping them from interacting with each other, and thus blocking the virus from fusing to the cell.

So at that stage, within days after the genetic sequence was made available, Dr. Ho's team started designing possible peptides. Dr. Ho also feverishly looked for a commercial lab that could actually produce and purify them quickly. He found a company in California, which he declines to name because, he says, he doesn't want it to be flooded by calls as it continues work refining the current peptides and new ones. Dr. Ho negotiated a price and repeatedly spoke with the company president to impress on him the urgency of the project.

The company managed to make 12 peptides, some in as few as 10 days, says Dr. Ho, adding that normally that is a process that takes weeks and sometimes months.

Meanwhile, Dr. Ho had flown to Hong Kong, as the city's chief executive had requested. Mostly, says Dr. Ho, he listened to Dr. Peiris and his research co-head, Yuen Kwong-yung. But Dr. Ho also presented his idea for the peptides, some of which were already under production. Dr. Peiris says he had also noticed that SARS fused with cells in a similar way to HIV and so was happy to collaborate on the experiment.

Back in San Francisco, the production company had run into a glitch. Peptides are made by lining up amino acids "like a string of pearls," says Dr. Ho, but someone at the company put a wrong amino acid on the string, ruining "two of the more important peptides." The company, says Dr. Ho, "made up for it" by working all weekend to redo them.

They finished just in time. That Monday, May 5, Dr. Ho made a second trip to Hong Kong, this time stopping over in San Francisco to "grab the peptides." After a grueling trans-Pacific flight, Drs. Ho and Zhang were in the Hong Kong lab of Drs. Peiris and Yuen first thing on May 7. Doing much of the actual lab work were two young scientists from Hong Kong University, Richard Kao and Leo Poon. China's health minister, Xu Guanhua, called Dr. Ho to see how the experiments were going.

By May 10, the researchers knew that two of the 12 peptides were very active against the SARS virus, approaching the test-tube efficacy of the new HIV drug Fuzeon, and three others also showed some promise. They also tested the peptides against HIV, where they didn't work at all, confirming that the peptides are specific for SARS. Speaking by phone late Monday night from his hotel in Beijing, Dr. Ho said that he and Dr. Zhang were busy designing refinements to the peptides "as we speak."

Ultimately, peptides may not be the ideal drug. Being a large molecule, they are hard and expensive to make. Small-molecule drugs, however, generally require extensive and time-consuming research to find drug targets. But even starting such work was impossible for Dr. Ho, because he didn't have the virus or any of its proteins. "We had nothing except the genome," he says.

--Karen Richardson and Antonio Regalado contributed to this article.

Write to Mark Schoofs at mark.schoofs@wsj.com

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