Twelve years ago, biologists and clinicians hoped for a fleeting moment that combining several new drugs might completely eliminate HIV from the body and thus achieve a cure. Those hopes quickly vanished when it was discovered that the virus hides in a dormant state inside certain cells out of reach of this therapeutic cocktail.
Ever since, researchers in the war against AIDS have looked for drugs to coax the elusive virus out of hiding so that other drugs or the patients' own immune systems could target them. But most of the meds were either toxic or ineffective. A few compounds derived from plants showed promise in the laboratory, but scientists could not procure sufficient quantities to move ahead with drug development.
New research points the way to addressing that scarcity. A Stanford University research team reports in Science that it successfully synthesized two plant chemicals that appear to lure HIV from its hiding spots. If the drug candidates prove themselves in human clinical trials, researchers say the process used to develop them may pave the way for the manufacture of commercial quantities of pharmaceuticals.
New synthesis methods constitute an important step in making plants and other natural products into practical therapies. Bristol-Myers Squibb's semisynthetic technique of making taxol for cancer treatment overcame objections of conservationists by eliminating the need to fell three Pacific yew trees to procure enough of the drug to treat one patient.
Prostratin, one of the compounds synthesized by the Stanford team, comes from the bark of the mamala tree (Homalanthus nutans), which is used by Samoan islanders to treat hepatitis. The other, 12-deoxyphorbol 13-phenylacetate (DPP), originates in resin spurge (Euphorbia resinifera), a cactus-like plant that is also being investigated as a painkiller. Prostratin has a storied history, because ethnobotanist Paul Cox, who found the plant during field studies in the early 1980s, has waged a campaign to ensure that Samoans receive a portion of the proceeds from any drug developed from the plant.
The availability of the plants is limited—intensive harvesting in Samoa could cause ecological damage—and, as with taxol, the amount of active chemicals that can be extracted is low. Stanford chemist Paul Wender and his colleagues synthesized prostratin and DPP by using oil from the seeds of a small Asian tree, Croton tiglium, as a starting material. Oil from the Jatropha plant, which can be used to make biodiesel, can also serve as an initial ingredient. Both provide readily available raw materials.
The researchers transformed croton oil into prostratin and DPP in a five-step process.
"We reduced the step count from around eight or nine steps to the four to five we ended with," Wender says. The synthesis technique is flexible enough that it can be altered to generate related chemicals that may demonstrate more effectiveness as drugs or a lower side-effect profile.
Both compounds have shown that they can induce HIV in cell cultures to emerge from its latent state and can protect healthy cells from becoming infected. The California-based AIDS Research Alliance, a non-profit that is trying to find new AIDS treatments, plans to move ahead with additional preclinical work on prostratin. The group cut a deal with the prime minister of Samoa in 2001 to return 20 percent of any prostratin-related profits to the country. This agreement is thought to be the first time local groups were given a stake in a compound discovered by traditional healers.
While promising, these drug candidates still have a long way to go before they become a routine weapon in the anti-HIV armamentarium.
"I'm skeptical about agents such as prostratin to flush out latent HIV," says Mario Stevenson, an HIV researcher at the University of Massachusetts Medical School in Worcester. "Firstly, we don't know what maintains HIV in a latent state and, until we do, we can't rationally design agents that interrupt latency. Secondly, I'd like to see proof of concept that these new prostratin analogs actually do affect latent HIV in a physiologically relevant setting."
Stevenson also notes that the reservoirs may exist in cells other than the white blood cells targeted by prostratinlike drugs.
"The upshot is that I think that the science behind designing drugs to flush out latent [HIV] is hampered by our limited understanding of the nature of latency itself," he says.
The investigation of synthetic prostratin and DPP will undoubtedly continue. With the much-publicized failure of an HIV vaccine last year, researchers are still desperate to find better ways to boost the effectiveness of AIDS therapies.