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Sep 10, 2013

Turning HIV from Latent into Active Form to Treat It

  • Scientists are looking to nature for new solutions to diseases such as AIDS, cancer, and Alzheimer’s, according to a presentation today at the American Chemical Society conference in Indianapolis. The goal is to tap into “3.8 billion years of chemical innovation that has created a large library of natural compounds,” said Paul Wender, Ph.D., Bergstrom Professor of Chemistry at Stanford University.

    Specifically addressing AIDS, Dr. Wender outlined a novel strategy, and what some would consider a revolutionary approach, to treat the disease.

    “We want to get to the source of the problem and eradicate the disease. Right now therapeutic strategies are focused on containing the infection,” he told the press conference. “We need to find the reservoir cells that contain latent HIV and then kill those cells. This should force the virus to express itself. We can then use a range of antiviral therapies to kill the virus in its active form.”

    His team has been working with an ingredient found in a medicinal tea brewed from tree bark by tribal healers on the South Pacific island of Samoa. The group developed a way to make the compound—prostratin—in large amounts from readily available ingredients.

    “Inspired by nature, we now have made synthetic variants, or analogs, of prostratin, that are 100 times more potent than the natural product,” explained Dr. Wender.

    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, continued Dr. Wender. 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.

    “That’s part of the basis for our approach to advancing potentially transformative treatments for AIDS, Alzheimer’s disease, and resistant cancer,” said Dr. Wender. “The mamala tree did not start making prostratin millions of years ago to treat a disease that appeared in the 20th 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.”

    Turning to Alzheimer’s, Dr. Wender noted that if the research community does not come up with a new solution in the immediate future, society will be looking at a bill for treating the disease that runs over a trillion dollars. “But the money isn’t the main thing,” he told the audience. “We’re losing lots of people to Alzheimer’s.”

    His team has been working with some novel compounds that were shown to induce the formation of new synapses in mice that then learn faster and remember information over time. “We are trying to discover new, first-in-class drug strategies for which no current solution exists,” he pointed out.

    Dr. Wender’s group is also involved 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,” said Dr. Wender, adding that his team has synthesized over 100 analogs of the compound. “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.”



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