Translating nature's library yields drug leads for aids, cancer, Alzheimer's disease

Speaking at the 246^th National Meeting & Exhibition of the American Chemical Society (ACS), Paul A. Wender, Ph.D., described efficient new ways of making prostratin and related leads, as well as other drug candidates first discovered in sea creatures, that appear even more effective for AIDS and have applications for Alzheimer's disease and cancer.

In his presentation, Wender focused on fundamentally new approaches to some of the most serious unmet health challenges of our time. He is with Stanford University. They include the eradication of AIDS, developing medicines that stop the progression of Alzheimer's disease and treating resistant cancer -- the major cause of chemotherapy failure for most cancers.

Wender leads a scientific team at Stanford University that first developed a way to make the tea ingredient, prostratin, in large amounts from readily available ingredients. He described how that initial synthesis broke down a major barrier to probing prostratin's antiviral effects. Until then, scientists had to extract prostratin from the bark of the Samoan mamala tree, and only tiny and variable amounts were so obtained. Samoa is where another scientist, Paul Cox, in 1987 heard a native healer praise mamala bark tea as a remedy for viral hepatitis. It led scientists at the National Cancer Institute to analyze the bark and identify prostratin as a key ingredient. Wender's synthesis of prostratin opened the door to research on the substance and enabled his team to change prostratin's architecture.

"We now have made synthetic variants of prostratin, called analogs, that are 100 times more potent than the natural product," Wender said. "That's part of the basis for our approach to advancing potentially transformative treatments for AIDS, Alzheimer's disease and resistant cancer. The mamala tree did not start making prostratin millions of years ago to treat a disease that appeared in the 20^th century. The same is true for other substances that occur naturally in plants and animals. But we now have the tools to read nature's library and use the lessons learned there to design, make and study new molecules that address unmet medical needs. This "function-oriented" approach seeks to identify useful parts of molecules and then, based on this knowledge, to design new and more readily synthesized molecules that work better or work in totally new ways. This is a well-validated strategy, perhaps best exemplified by the emergence of modern aviation from knowledge of how birds fly."

Those new versions of prostratin show promise in laboratory tests for both preventing HIV from infecting human cells and awakening dormant HIV viruses that are hiding inside human latently infected cells. Latent HIV cell reservoirs are untouchable by today's antiviral medicines. Antiviral medicines reduce active virus levels in patients' blood and keep patients healthy. But when patients stop the medication, the hibernating HIV in reservoirs awakens to resupply active virus. Prostratin flushes HIV out of its cellular sanctuaries so that antiviral drugs can attack and hopefully eradicate the HIV from the body. In essence, if one wants to eliminate a weed, one needs to get rid of its roots.

Wender's group used those same "function-oriented" approaches in the design and synthesis of analogs of bryostatin, a substance that occurs naturally in sea creatures called bryozoans.

"Bryostatin has shown great promise in laboratory experiments as the basis for development of potentially transformative medicines for cancer, Alzheimer's disease and the eradication of HIV/AIDS," Wender said. "However, its limited supply from natural sources has slowed research, and as with prostratin, it was not evolved in nature for modern therapeutic use. We have overcome both the supply and performance barriers by designing simpler and thus more readily synthesized analogs of bryostatin -- over 100 of them so far. When tested in various assays related to HIV/AIDS eradication, these analogs are up to 1,000-fold more potent in flushing HIV out of its hiding places than prostratin. Much needs to be done, but we are on a promising trajectory."

Wender's group is working with colleagues at the National Institute of Allergy and Infectious Diseases, the UCLA Center for AIDS Research and the Collaboratory of AIDS Researchers for Eradication to conduct further studies on the analogs. The AIDS Research Alliance, an independent not-for-profit research organization, is advancing prostratin toward clinical trials.

The research team is currently also focusing on bryostatin and designed analogs for their potential use in boosting memory in Alzheimer's patients. The compound is known to improve learning and memory in laboratory rats. It appears to cause formation of new connections in the brain that are associated with learning and memory. Wender noted that bryostatin and its analogs may also have benefits for people who have had strokes or other conditions in which learning and memory are impaired.