Dr. Ian Tietjen came to Wistar in 2019 as a research assistant professor in the laboratory of Dr. Luis Montaner. He brings a fascinating approach to HIV and infectious disease research that explores the traditional medicine knowledge of Indigenous peoples and healers around the world in treating infection with natural substances.
"There is a wealth of information and experience that has been passed down through different cultures over generations and allowed people to maintain health and treat disease before the advent of modern medicine," said Tietjen. "While a lot of this information can be anecdotal and sometimes inexplicable to scientists like us, we believe it could hold the key to powerful medicines. We want to apply our scientific method and currently available research technologies to find out."
Many natural compounds have provided antiviral activity during evolution, for example to protect plants and other organisms that don’t have a specialized immune system like ours and use chemicals to fight viruses. Therefore, these substances could be repurposed as antivirals to support our immune response against infection.
Based on this idea, botanists and chemists began teaming up in the 1940s to create antiviral drugs using chemical compounds found in plants, and during the past 25 years, several screening programs have investigated the antiviral activity of medicinal plants.
Dr. Tietjen brought to Wistar a collection of compounds derived from plant and marine organisms that he obtained in collaboration with other researchers around the world and while working with traditional healers in different countries. The Montaner lab is now testing these substances for their ability to affect the immune response to HIV.
When COVID-19 started, Drs. Tietjen and Montaner decided to apply the same approach and comb through the library to look for antiviral activity against SARS-CoV-2. For example, they are testing for the ability of these compounds to disrupt the interaction between the viral Spike protein and the ACE2 receptor present on human cells — the lock and key mechanism that allows virus entry — in order to halt infection.
"So far, we’ve found several pure compounds that are able to do so in the laboratory," said Tietjen. "We also identified several African medicinal plant extracts that disrupt this interaction."
This was accomplished in collaboration with Joel Cassel in Wistar’s Molecular Screening Facility. Cassel successfully adapted a pre-existing assay for large-scale screening, which allowed the team to evaluate many compounds and find positive hits quickly. To confirm the screening results, they tested those hits against a different receptor/viral protein interaction, and many of them didn’t show activity in this experiment, indicating they specifically block the SARS-CoV-2 entry mechanism.
"Importantly, we are observing similar bioactivities in specimens of the same plant collected from different healers and in different locations, which supports that the bioactivity is intrinsic to the plant," said Tietjen.
Some of the medicinal plant extracts are extremely potent, in some cases disrupting the Spike/ACE2 interaction at very low concentrations.
"One of our leads includes a species of Artemisia, a family of plants commonly known as mugwort, wormwood and sagebrush and well established as an antimalarial agent. Our observation is consistent with what others are reporting worldwide, although it’s way too early to recommend use of this plant to treat COVID-19," said Tietjen.
He added that some healers in Southern Africa have administered some of the medicinal plants being tested at Wistar to community members that have been coming to them recently with respiratory infections, and they report having obtained benefits.
"This information is anecdotal, so we have to discuss our findings together and all agree on a plan to monitor these observations more closely," Tietjen said. "This is the perfect example of the benefits of what we call ‘reverse pharmacology’ efforts — we obtain compounds and information by collaborating with traditional healers, test their products in the lab with our methods and share our results with them as the data are generated to inform their practices in real-time."
Tietjen also emphasizes that collaborations with healers and their communities involves years of building relationships and trust. It also requires working together as equal partners and toward mutual knowledge benefits. "This exchange, being able to provide this kind of information to healers, and also learning about quite different but also valid ways to perform medicine are very rewarding aspects of this work," he continued. "We can learn a lot from each other."
In the lab, researchers are now confirming preliminary results using a SARS-CoV-2 pseudovirus — virus-like particles that have the essential components for infecting cells in culture but can’t replicate and cause further infection, representing safe tools to mimic SARS-CoV-2 virus for further studies.
Tietjen, Montaner and team are also working to determine if the hit compounds can block entry of the real SARS-CoV-2 into cells in vitro. This work can be done at Wistar in the BSL3 facility, which provides the required safety environment for handling airborne infectious diseases like coronaviruses.
Next, researchers plan to refine and optimize the most potent molecules to make them as selective and safe as possible.
A longer-term goal is to identify agents that can enhance the antiviral activity of existing drugs like remdesivir, along with those that could inhibit entry of other coronaviruses that use ACE2 for entry. Those leads would eventually go into animal models to test for in vivo efficacy.
"Our work looking for natural antivirals is worthwhile because, even when a SARS-CoV-2 vaccine becomes available, it won’t be accessible to everyone immediately, especially in resource-limited regions where people rely on traditional medicines and community healers for their health," said Tietjen. "Also, since the world has been hit by different coronavirus outbreaks since 2003, it’s critical for us to build up our antiviral armamentarium and be prepared for the next potential coronavirus threat to human health."