Maintaining a weed-free yard is a constant chore. Pesticides can keep weeds on the surface at bay, but they don’t get rid of seeds and roots lurking underground that grow up at their whim.
Treating HIV has a similar problem. While combination antiretroviral therapy (cART) stops the spread of the active virus, it doesn’t target latent virus reservoirs lurking in CD4+ T cells that evade the immune system. These reservoirs can spontaneously reactivate and replicate, requiring chronic administration of cART to manage HIV.
Forcing the dormant virus (or weed) to show itself in order to get rid of it once and for all would enable long-term remission of HIV (or a lawn effortlessly worthy of neighborhood envy). Researchers are developing small molecule drugs that can force the latent virus to turn on, causing the host cells to undergo apoptosis or an immune attack. While the cells are killed weedwhacker style, cART keeps the newly active virus from spreading and replenishing the reserve of dormant virus. Although several of these virus-coaxing drugs (called latency reversal agents or LRAs) have been tested as an HIV cure in humans, they haven’t significantly reduced viral reservoirs and can carry toxic side effects.
In a recent study in the Journal of Natural Products, researchers reported a potent new LRA compound isolated from a sea sponge (1). Their work provides a starting point for the development of a new HIV therapy and illustrates the value of natural chemical diversity in drug discovery.
“It's another prime example of how we may now have a way forward with curing HIV that we never would’ve without mother nature giving us some hints,” said Bill Baker, a natural product chemist at the University of South Florida who was not involved in the study.
Chemical compound libraries from natural sources have higher rates of antiviral activity than synthetic molecules, said Ian Tietjen, a molecular and cell biologist at the Wistar Institute and coauthor of the study. “A tree or a sponge doesn’t have an immune system like you or me, so they rely a lot more on chemical compounds to fight off viruses,” he said. “Nature has already done the work for us, so we should take advantage of that to look for antivirals.”
Ian Tietjen integrates natural products into his search for antiviral drugs.
credit: The Wistar Institute
The researchers did just that, screening an array of crude extracts and pure products from marine invertebrates for LRAs. “The marine environment gives you new chemical scaffolds with very promising biological activity,” said Raymond Andersen, a natural product chemist at the University of British Columbia and coauthor of the study. “The power of looking in the ocean is that you find things that you wouldn't find otherwise.”
The team observed that an extract from a Phorbas marine sponge collected from Howe Sound off the west coast of Canada showed latency reversal activity. They then separated the extract into multiple components and tested each one, repeating the process until they had isolated the active compounds. After extensive analysis of their chemical structures, the researchers identified the compounds as a class of molecules called sesterterpenoids.
The researchers tested the compounds in a CD4+ T cell line and found that two were more effective at activating latent HIV virus than the established LRA prostratin (another natural product derived from the bark of the mamala tree that Samoans have long used as an antiviral) (2). They observed that the activity of their compounds was blocked when they added an inhibitor of protein kinase C (PKC), indicating that these new LRAs work by activating PKC. Finally, the researchers tested the most potent compound, dubbed ansellone J, in CD4+ T cells donated from four people living with HIV and undergoing cART treatment. Ansellone J activated latent virus to a similar degree as prostratin, but at a 10-fold lower concentration.
The potency of ansellone J in real HIV cells from donors is a powerful demonstration of its therapeutic potential, according to Baker. “That's probably the real coup de grâce in this paper,” he said. However, if the compound is developed into a commercial drug, its structure will need to be adjusted in order to synthesize it on a large scale and protect it as intellectual property, he added.
Andersen’s team is working on developing novel and superior analogs of ansellone J. “We basically start clipping parts off of the natural product until we find out what's the minimum structural requirement to give us the biological activity,” he said. They can then add features to this core structure that enhance the molecule’s synthetic feasibility, patentability, and pharmaceutical properties.
David Margolis, an infectious disease clinician and HIV scientist at the University of North Carolina who was not involved with this study, would like to see ansellone J tested in a greater number of HIV donor cell samples and compared to other common LRAs. Like previous PKC activators, the toxicity of the compound might be too high for clinical use, Margolis added. “Trying to find some way to get to more effective compounds that are also safe is a major challenge,” he said.
While PKC activators can trigger dangerous non-specific immune responses, preliminary data suggest that combining low doses of LRAs that operate through separate mechanisms can increase the activity and decrease the toxicity of each, Tietjen said. He hopes that a more potent PKC-targeting LRA could lead to a safer drug cocktail.
For Tietjen, the search for a cure for HIV isn’t over until the depths of the ocean have been explored. “We do have some leads; we have some things that we can test; we have some new therapies that we can continue to try,” he said. “The next one is probably not going to cure HIV, but each one is pointing us to a closer and closer direction, and we are making progress.”
References
- Wang, M. et al. Ansellone J, a potent in vitro and ex vivo HIV?1 latency reversal agent Isolated from a Phorbas sp. marine sponge. J Nat Prod 85, 1274-1281 (2022).
- Cox, P. A. Ensuring equitable benefits: The Falealupo covenant and the isolation of anti-viral drug prostratin from a Samoan medicinal plant. Pharm Biol 39, 33-40 (2001).
