Stanford researchers synthesize compound to flush HIV out of hiding

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."

Wender's team developed their method of synthesizing prostratin and DPP by using a renewable resource, croton oil, made from the seeds of a small tree (Croton tiglium) cultivated in Asia. They derived phorbol from the croton oil and then converted it into the structure of prostratin.

The conversion process required some engineering finesse; they had to overcome a hurdle when, by removing an oxygen atom, they triggered a series of anticipated but seemingly undesired changes.