The Pan-African Natural Products Library compounds oleanolic acid, poinsettifolin B, and rhuschalcone III disrupt SARS-CoV-2 Spike-host ACE2 interactions and SARS-CoV-2 replication
Screening of the pan-African Natural Products Library identified three compounds—oleanolic acid, poinsettifolin B, and rhuschalcone III—that selectively disrupt SARS-CoV-2 Spike-ACE2 interactions and inhibit viral replication, offering promising antiviral leads for resource-limited settings.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer
Viruses are masters of disguise and intrusion, but they cannot infect a human cell without first finding a specific door to knock on. For the virus that causes COVID-19, that door is a protein on the surface of our cells called ACE2. The virus carries a key, a spike protein, which must lock perfectly into this door to gain entry. If scientists can find a substance that jams that lock or blocks the key, they can stop the infection before it begins. This is the logic behind searching for new antiviral medicines, a task that becomes even more urgent in regions where access to vaccines and modern treatments is inconsistent. Nature has long been a source of such medicines, offering a vast library of chemical compounds produced by plants to defend themselves against pests and diseases. Researchers often look to these natural defenses for clues on how to protect humans, turning to the rich biodiversity of the African continent to find new ways to fight viral invaders.
A team of scientists set out to explore this potential by testing a specific collection known as the pan-African Natural Products Library. This library contains over 500 pure chemical compounds extracted from medicinal plants found across Africa. The researchers wanted to see if any of these natural substances could interfere with the virus's ability to attach to human cells. They focused on the moment the viral spike protein tries to bind to the ACE2 receptor, a critical step that allows the virus to enter the cell and start replicating. To test this, they mixed the viral spike protein and the human receptor protein together in a lab dish, along with small amounts of the plant compounds. If a compound worked, it would prevent the two proteins from sticking together, a result that could be measured by a change in light emitted by the mixture.
From the hundreds of compounds tested, three stood out as particularly effective at breaking the connection between the virus and the cell. These were oleanolic acid, poinsettifolin B, and rhuschalcone III. Oleanolic acid is a type of compound found in many fruits and plants, while poinsettifolin B comes from a herb native to the forests of Cameroon and Gabon, and rhuschalcone III is derived from the root bark of a shrub used in South Africa to treat seizures. The researchers found that these three substances stopped the viral protein from binding to the human receptor at very low concentrations, specifically between 0.5 and 2.4 micromolar. Importantly, they tested these compounds against a different, unrelated pair of proteins that the immune system uses to communicate, and found that the plant chemicals did not interfere with that process. This suggests the compounds are selective, targeting the virus specifically without disrupting other essential biological functions.
The team then moved beyond the protein interaction tests to see if these compounds could actually stop the virus from multiplying inside living cells. They infected a line of monkey kidney cells with the virus and added the plant compounds to see if the cells survived. Oleanolic acid and rhuschalcone III both showed the ability to reduce the amount of virus produced by the cells without killing the cells themselves at low doses. Poinsettifolin B, however, did not stop the virus from replicating in this test, even though it was good at blocking the initial protein binding. The researchers noted that while oleanolic acid was effective, it became toxic to the cells at higher doses, limiting how much could be used. Rhuschalcone III showed a more consistent, though weaker, ability to inhibit the virus without causing immediate harm to the cells at the concentrations tested.
To understand how these molecules worked, the researchers used computer models to visualize how they might fit into the space where the viral spike and the human receptor meet. These simulations showed that all three compounds interact with specific parts of the proteins that are crucial for the virus to attach. The models suggested that the compounds fit into the binding site through a combination of physical shape and chemical attraction, with the shape of the molecules playing a major role. Interestingly, the computer models indicated that oleanolic acid binds to parts of the viral protein that have remained the same across different variants of the virus, including the highly mutated Omicron strain. This suggests that oleanolic acid might remain effective even as the virus changes over time. In contrast, the other two compounds interact with parts of the protein that have mutated in newer variants, which might make them less effective against future strains, though this has not yet been tested in the lab.
The study also looked at whether small changes to the structure of rhuschalcone III could make it an even better inhibitor. By using computer programs to generate thousands of similar molecules, the researchers identified several new candidates that appeared to bind even more tightly to the virus-receptor complex than the original compound. These simulations suggested that tweaking the chemical structure could improve the drug's ability to block the virus. While these new molecules exist only as computer models at this stage, they offer a roadmap for chemists to design better versions of the natural compounds. The work highlights that the medicinal plants of Africa hold a reservoir of chemical diversity that can be tapped to find new tools against viral diseases, providing a potential source of treatment that could be developed locally for communities that need it most.
Drowning in papers in your field?
Get daily digests of the most novel papers matching your research keywords — with technical summaries, in your language.