Devising Drugs

Whe

n scientists sequenced the genome of the SARS coronavirus in April, the medical community hailed the achievement for its startling swiftness, announcing the first step on the road to defeating the disease had been taken. A little more than a month later, however, little has changed for SARS patients in Asian hospital wards and ICUs. Diagnostic tests are still slow or unreliable. Treatment for the disease—a combination of steroids and ribavirin—hasn’t proved very effective and has barely been modified since the early weeks of the outbreak. The best tools for stopping SARS are still face masks, fever checks and quarantine—19th century medicine for a 21st century disease.

Scientists may be closing the gap, though. Last week German scientists reported that an experimental cold-fighting drug might be able to stop the virus from replicating inside infected cells. Earlier in Hong Kong and mainland China, renowned AIDS researcher Dr. David Ho announced that a modified HIV treatment had the potential to block the virus from infecting human cells in the first place. Although both treatments are still unproven, they show that the SARS coronavirus is vulnerable—and that tapping its genome will eventually reveal its weakest strand. “The interesting part is the fact that you can go from finding the virus in just a few weeks, to the viral genome in a couple of weeks, and now use that genome information to target designer drugs,” says Dr. Malik Peiris, a microbiologist at the University of Hong Kong (HKU) who helped identify the coronavirus.

Because viruses can’t be killed in the same way as bacteria, one of the best ways to stop them is to disrupt their replication, the viral copying process that eventually destroys an infected cell. A study of SARS’ genetic structure suggests the coronavirus needs an enzyme called protease to make copies of itself, which is how the virus spreads inside a victim. Create a drug that neutralizes the protease enzyme, and you may be able to halt the disease in its tracks.

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That’s what Dr. Rolf Hilgenfeld and his associates in Germany are trying to do. The researchers examined the coronavirus genome and developed a theoretical compound that could act as a protease inhibitor. By searching for compounds with a similar chemical structure, they quickly found an existing cold drug called AG7088, developed but never marketed by the drug company Pfizer, that might similarly interdict the coronavirus’ protease—giving researchers a potential weapon against SARS. “The compound itself will probably not be used for a drug to treat SARS,” said Dr. Hilgenfeld. “But it is a very good starting point for designing drugs that fit better.”

Ho, scientific director of the Aaron Diamond AIDS Research Center and a pioneer in the early use of the AIDS cocktail, might already have one of those drugs. Even better than stopping a virus’ replication is preventing infection in the first place. The coronavirus attacks cells by latching onto receptors on a cell’s surface, fusing with the cell and then infecting it. Ho believes custom-designed peptides—snippets of proteins—might be able to block the virus from interacting with the cell receptors. Called fusion inhibitors, the compounds are being used with success in HIV patients.

Ho has been looking for a way to help doctors in China since the outbreak began. When he examined the published SARS genome in mid-April, he saw his chance. Ho noticed that a gene in the coronavirus responsible for viral fusion was very similar to the same kind of gene in HIV. If peptide fusion inhibitors worked with HIV, Ho reasoned, they might work with SARS. He ordered peptides of his own design from a company in California that labored overtime to produce the compounds, some in as quick as 10 days. (The process often takes months.) On May 5, Ho and a colleague picked up the peptides and flew to Hong Kong, where they immediately began testing them at HKU on laboratory cells infected by SARS. “To our great excitement, we found the peptides that were predicted to do the job did the job,” says Peiris.

Ho took his peptides to the Chinese Academy of Medical Sciences in Beijing, where animal tests began almost immediately. “We had this wonderful result to share with them, and they were mobilizing to see if they could get the monkey study ready quickly,” Ho says.

But even with mainland China’s somewhat lax regulations for drug approval, it will likely be a year or more before the peptide fusion inhibitor could be used for patients. And that assumes the coronavirus won’t evade the treatment through mutation. Dr. Edison Liu, executive director of Singapore’s Genome Institute, which recently published a study comparing the coronavirus genome in several different regions, says, “If the receptor interaction is changed so that the virus uses a different receptor or has a different region to which it binds, it’ll evade the peptide.”

Peptides and protease inhibitors won’t help the victims of the current SARS outbreak, who’ll have to make do with ribavirin and steroids. But with all 29,700 or so nucleotides of the SARS genome already available for every researcher in the world to see and analyze, useful treatments should come quicker than ever before.