Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
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The Wall Street Journal - 19 Sep 1996
Jerry E. Bishop, Staff Reporter of The Wall Street Journal
The targets of the race are members of the herpes family of viruses. These include viruses that cause cold sores, genital herpes infections, chickenpox, shingles and infectious mononucleosis. The basic research advance involved one of the herpes viruses called cytomegalovirus, or CMV, which causes blindness in AIDS patients and can be serious or even fatal for cancer and organ-transplant patients, especially children, whose immune systems are suppressed by medications.
Three separate teams of drug-company scientists reported simultaneously that they may have found a weak spot in the CMV that might be attacked with drugs. The same Achilles' heel probably exists in all the related herpes viruses, potentially making them vulnerable to specially designed drugs.
The reports were published by researchers at SmithKline Beecham PLC laboratories in King of Prussia, Pa., by researchers at the Ridgefield, Conn., laboratories of the German-owned Boehringer Ingelheim GmbH, and by researchers at the Searle division of Monsanto Co. in St. Louis.
In addition to the big drug-company research teams, scientists with at least two biotechnology companies, Agouron Pharmaceuticals Corp. in San Diego and Arris Pharmaceutical Corp. in South San Francisco, Calif., are racing along the same path to drugs to thwart the herpes viruses. Agouron researchers are working with scientists of Japan Tobacco Inc. in Osaka, Japan.
The researchers are following the same strategy that has led to new breakthrough drugs, called protease inhibitors, that are being successfully wielded against the virus that causes AIDS. The strategy involves finding a drug that will inhibit or block the action of a protein that the virus must use to reproduce itself after it has infected a healthy cell. By inhibiting the virus's reproduction, the drug prevents the infection from spreading to other cells and thus, it's hoped, stops the disease.
Researchers have known for several years that when a herpes virus infects a human cell, it forces the cell to make a unique protein, called a serine protease. The unique protein paves the way for the virus to be reproduced by chopping a large protein into smaller pieces. The protease used by the herpes viruses differs by a few molecules from that used by the AIDS virus for its reproduction.
In separate reports published in this week's issue of the scientific journal Nature, the three drug-company teams each said they had determined the three-dimensional structure of the protease used by the CMV and, presumably, by most of the other herpes viruses. Agouron in San Diego said its researchers have also described the structure of the CMV protease in a report in the biology journal Cell.
"We now know where every single atom [of the protein] is located," explained the head of the SmithKline Beecham team, Sherin Abdel-Meguid, an expert in the X-ray technique used to locate each atom in a molecule.
What is exciting the researchers is that the newly seen structure revealed that the cutting-edge part of the CMV protease, its "active site," is a set of three molecules that are distinctly different from the molecules other proteases use to chop proteins in two.
This raises the likelihood that drugs could be designed that would block the cutting action of the CMV protease without interfereing with any other proteases that the cell might need for its normal operations. Such highly selective protease inhibitors could block the spread of the virus while causing few, if any, adverse side effects. And because all the herpes viruses use similar proteases, similar or even identical drugs should work against most herpes infections, the researchers hope.
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