United Press International - Thursday, July 11, 2002
Ed Susman, UPI Science News

"We saw no adverse experiences at all in the first few healthy volunteers who were given the drug," said Stephen Young, senior director of the medicinal chemistry department of Merck and Co. Inc. of West Point, Pa., which is developing the drug.

"We expect to begin pilot studies with HIV-infected patients later this year," Young told United Press International at the 14th International AIDS Conference. He said these studies would probably enroll about 20 patients to receive the experiemental compound known as an integrase inhibitor.

New drugs target the actions of the enzyme integrase, one of three critical proteins required by the human immunodeficiency virus, which cause AIDS, to turn human cells into factories that produce more HIV.

Scientists already have created drugs that attack reverse transcriptase and protease, the other HIV enzymes, which are related to the life cycle of the retrovirus's reproduction. Zidovudine, better known in the United States as AZT, was the first of the anti-retroviral drugs developed to fight the disease.

AZT is a reverse transcriptase inhibitor. Protease inhibitors, when used in combination with drugs such as AZT, revolutionized treatment of people with HIV in the developed world.

Young said the drug being developed by Merck follows a long molecular history. Integrase is involved in three functions, the final step being the transfer of the so-called integrase strand of DNA. "The integrase enzyme," he explained, "takes prepared DNA and inserts it into the host cell DNA." Once accomplished, the cell begins the process of churning out HIV.

The new drug, designated as L-870810, prevents that insertion from occurring. Instead, the viral strand floats around the cell until molecular processes connect the two ends of the strand forming it into a circle -- a procedure called non-homologous end-joining.

Researchers from Shinogi USA Inc. in Florham Park, N.J., also presented studies conducted on healthy volunteers. Shinogi's drug, designated as S-1360, was well-tolerated by the subjects who received the compound, the researchers said.

"We've been waiting for integrase inhibitors for a long time," said Dr. Robert Murphy, professor of medicine at Northwestern University School of Medicine, Chicago. "The early work with these integrase inhibitors look good. It is something that I think will be a benefit to patients."

The prospect of integrase inhibitors was first discussed at the 11th International AIDS Conference in Vancouver, B.C., in 1996, but years followed without any of candidate compounds reaching the clinic.

Daria Hazuda, executive director of the department of biological chemistry at Merck, explained scientists first looked at drugs called diketobutanoic acids as possible agents to interfere with integrase strand processing. Those drugs proved too difficult to work with, however, so Merck scientists developed other compounds that did the same things as the diketo acids.

The new compounds, called naphthyridine carboximides, included L-870810, "which has very good potential for clinical activity," Hazuda said. Earlier examples of the compounds showed efficacy in animals, she said.

Young said researchers are interested in L-870810 because in test tube studies it appeared effective against strains of HIV that were resistant to other drugs and various natural strains of HIV found in diverse parts of the world.

He said the company expects Food and Drug Administration approval to proceed with further clinical studies.
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