New Compounds Inhibit HIV in Lab.
Scientists at Merck Research Laboratories in West Point, Pa., now report the discovery of two new compounds that sabotage the third viral enzyme, called integrase. By blocking integrase, these compounds interfere with the replication cycle of HIV-1, the most common strain of the virus. Although the researchers so far have confined their experiments to cells in laboratory dishes, the compounds are the first to clearly render integrase incapable of splicing viral DNA onto host-cell DNA.
"I think this is very promising," says W. Edward Robinson Jr., a virologist at the University of California, Irvine whose research team in 1996 isolated a less promising compound that blocks integrase. "This, combined with our data and [other findings], suggests we are getting closer to having molecules that act against integrase--and which can be used in people."
Tapping a corporate repository of natural and artificial chemicals, the Merck researchers tested roughly 250,000 substances before finding two that worked well. These acids, called L-731,988 and L-708,906, inhibited integrase in chemical tests. They also prevented for several weeks the spread of HIV grown in cell cultures and quelled strains of HIV that are resistant to other enzyme inhibitors, the scientists report in the Jan. 28 SCIENCE.
Upon entering an immune cell, HIV makes a DNA version of its viral genome. In the nucleus of the cell, HIV cleaves the host's DNA chain and, guided by integrase, inserts its DNA into the host genome.
Under direction from this integrated viral DNA, the cell changes its priorities and starts producing RNA and proteins that make copies of HIV. The newly created viruses then find their way out of that immune cell to infect others, spreading disease throughout the body. Complete takeover of a cell takes less than 1 day, says study coauthor Daria J. Hazuda, a Merck virologist.
By examining the virus at various stages of its initial cell conquest, the researchers determined that the two new drugs halt HIV by keeping its DNA from attaching to the host cell's DNA.
To prove the drugs work by inhibiting integrase, the researchers incubated some HIV-infected cells with L-731,988 or L-708,906. Most but not all of the viruses died. The researchers found that surviving viruses produced a modified form of integrase that is resistant to the chemical--establishing that the compounds had been disabling the integrase in the original HIV.
Merck officials are cautiously optimistic. "We are a long way from having a clinical drug," says spokesman Laurence J. Hirsch. "We're still looking for better leads, better compounds."
The study should stimulate chemists to examine the chemical family--called the diketo acids--to which L-731,988 and L-708,906 belong, says pharmacologist Yves Pommier of the National Cancer Institute in Bethesda, Md. Other diketo acids or their derivatives might serve as more potent integrase inhibitors.
Although integrase has no direct counterpart in mammals, its inhibitors might adversely affect some mammalian enzymes, Robinson says. Such drugs would need to avoid blocking DNA-binding proteins in people. Tests on animals could reveal such problems, Robinson says.
Scientists must also determine whether chemicals that thwart integrase can work in concert with other enzyme inhibitors. "The days of single-drug therapy are long gone," says Robinson.
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|Date:||Jan 29, 2000|
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