Any hunter will tell you that when your quarry goes into hiding, you have to flush it out to get a good shot at it. Such is the case with HIV, the virus that causes AIDS.
Though antiretroviral "cocktails" can target an active infection, they cannot get at the virus when it retreats inside the host's T cells, where it may lie dormant for decades, waiting for an opportunity to burst forth in a fresh round of infection. What HIV hunters need is a good bird dog.
Now, Stanford chemist Paul Wender and his coworkers have found a way to synthesize better bird dogs, agents that can be tailored to flush HIV out into the open where the immune system and antiretroviral therapies can destroy it. Wender is senior author of a paper about the research in the May 2 issue of Science.
"We're not sure how far this will go, but certainly, from a theoretical point of view, it has promise of taking therapy to the next level-that is, addressing issues related to eradication of the disease, of the virus, at least," said Wender, the Francis W. Bergstrom Professor.
Wender and his co-workers Jung-Min Kee and Jeff Warrington have developed a way to synthesize prostratin and DPP, two compounds that occur naturally in plants, in the laboratory. Prostratin, found in the Mamala plant (Homalanthus nutans) that grows in the Samoan rainforest, has shown promise in previous studies as an activator of dormant HIV. DPP, a molecular relative of prostratin found in resin spurge (Euphorbia resinifera), which grows in arid regions, also has shown potential.
Research has been hampered, though, because the compounds are difficult to obtain, particularly in the quantities needed for practical lab work on their mode of action and therapeutic potential. The yield from both plants is low and highly variable; the availability of the plants is limited; and isolating the compound is difficult. Heavy harvesting of the wild plants, especially in Samoa, also could cause ecological damage.
But synthetic prostratin and DPP, which now can be readily made in the lab, changes that equation.
"We have now minimized, if not eliminated, the issue of availability of prostratin and DPP," Wender said. "But equally, if not more importantly, we have opened access to other compounds that might be similar in structure but superior in function."
Previous work done in mice by researchers at the University of California-Los Angeles indicates that prostratin, used in combination with interleukin-7, an immune system stimulator made in bone marrow, managed to flush out and eliminate approximately 80 percent of the dormant virus. But with HIV, 80-percent efficiency is not enough. Anything less than 100 percent means the virus is still lurking in the T-cells and will spring back to action as soon as an opportunity presents itself.
"Nature has produced these compounds for various reasons in the plants from which they're derived, but certainly not to treat human maladies," Wender said. "They're not optimized for human therapy."
But with synthetic prostratin and DPP available, researchers can take the basic compounds and tinker with the structure and related function. "We could find out how to improve them by reverse engineering: figuring out what is important and what isn't important," Wender said. "We could begin to design and synthesize molecules that would never be found in nature but might actually be therapeutically more beneficial than what has been found thus far."
In the Science paper, Wender and his team detail how both compounds can be synthesized, but also show the initial phase of designing and making new derivative compounds.
Although prostratin has long been used by traditional Samoan healers without their patients experiencing acute side effects, it is possible that undesirable effects could show up in an immune-impaired patient taking prostratin or DPP. But Wender noted that engineering the compounds in a lab would permit scientists to circumvent these problems. "Usually these kinds of side effects are a result of a drug hitting multiple targets. So it hits one target, which is beneficial, but then it hits some other target, too," he said. "But by modifying the structures, you could select for the beneficial activity over the non-beneficial activity."
"It's a little bit like draw poker," Wender said. "The important point is that we're not forced to use the hand we get. We'll get a hand and we'll return a few cards if we don't like it, because we can keep on tuning this until we get it right, so that a royal flush, hopefully, can be realized."