Desert plants are a treasure trove in the search for new drugs

Environment and sustainability 23. aug 2022 3 min Professor Dan Stærk Written by Morten Busch

Desert plants have evolved in isolation in the Australian outback for millennia. They must simultaneously protect themselves from solar radiation, voracious herbivores and pathogenic bacteria while attracting pollinating insects. A new study found that a small shrub with stiff and tangled branches, small purple flowers and spatulate leaves is a treasure trove of unique natural compounds. An initial screening reveals several compounds that may be effective against bacterial infections, cancer and diabetes. While specific compounds are being scrutinised for their potential medicinal effects, improvements to screening methods continue to expand the range of new natural products from this unique Australian flora.

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Drought, fire and cold. Surviving in the Australian desert is a constant battle against extremes. To survive, desert plants develop specialised molecules – bioactive natural compounds – as chemical weapons to protect the plants from the extreme climate and fight the many enemies that can harm them. For thousands of years, the Australian Aboriginal peoples have used their knowledge of these plant species for medicinal purposes. In recent decades, the potential of nature’s virtually inexhaustible source of unique bioactive compounds has increasingly become so apparent to researchers that the search for bioactive natural products is now intensifying with the potential to become the sustainable drugs of the future.

“Up to 70% of all small molecules used in modern drugs to fight infectious diseases and cancer come directly or indirectly from nature. Through the evolution of plants and microorganisms, nature has blessed us with miniature chemical factories for the sustainable production of tomorrow’s medicines. In Australia, Eremophila plants are especially promising because of their adaptation to grow in the most climatically extreme areas of the continent. Our research therefore targets new bioactive natural compounds in Eremophila, and we are investigating their potential for diseases such as type 2 diabetes, infectious diseases and cancer,” explains Dan Stærk, Professor and Head of the Natural Products Research Group, Department of Drug Design and Pharmacology, University of Copenhagen.

Like a cup of coffee

Eremophila (Scrophulariaceae family) is a genus with more than 200 known plant species from the arid and semi-arid areas of Western Australia. Dan Stærk and colleagues have isolated more than 200 bioactive natural products from Eremophila. Some of these have shown antimicrobial and cytotoxic properties that potentially make them candidates for future antibiotics and anticancer drugs.

“The plants are especially rich in terpenoids, which are molecules with a skeleton of building blocks of five carbon atoms: an isoprene unit. In the search for the sustainable drugs of the future, sesquiterpenoids made from three isoprene building blocks and diterpenoids made from four isoprene building blocks are especially promising,” says Dan Stærk.

This study focused on caryophyllane sesquiterpenoids, a skeleton known since the discovery of beta-caryophyllane in 1834. This is present in both cannabis and rosemary and has analgesic and antimicrobial properties. Other caryophyllane sesquiterpenoids isolated so far have shown many pharmacological properties, including chemopreventive effects, and it is known that Australian Aboriginal peoples used plants with these compounds for medicinal and ceremonial purposes.

“In particular, Eremophila spathulata has not previously been studied phytochemically. We analysed an extract of the plant using high-performance liquid chromatography to separate the constituents of the complex extract and nuclear magnetic resonance spectroscopy to determine the three-dimensional structure of the isolated compounds. The extract contained many chemical components, just like a cup of coffee. Later in the process, we hope to find the bioactive natural compound – like the caffeine in coffee – that has the desired pharmacological properties,” explains Dan Stærk.

Very diverse and complex

In the initial studies, the researchers found seven previously unreported caryophyllane-type sesquiterpenoids that could potentially have pharmacological properties.

“Now that we have identified several new compounds in Eremophila spathulata, the next step is to determine whether they have pharmacological effects, and if so, what they are. We use polypharmacological screening to investigate whether the extract has the right “key”, which involves testing the extract in microplates with wells, each containing a pharmacological “keyhole”. These pharmacological keyholes may be related to combating metabolic disorders such as diabetes, diseases of the nervous system, bacterial infections and cancer – including combating antimicrobial resistance in bacterial infections and cancer – or something entirely different,” says Dan Stærk.

The researchers will then link high-performance liquid chromatography and polypharmacological screening, resulting in biochromatograms that can be used to identify the compounds with pharmacological properties. The researchers recently discovered a compound in the related plant Eremophila galeata that was effective against the breast cancer resistance protein that makes some cancer cells resistant to chemotherapy, so Eremophila has enormous potential for finding new drug candidates.

Eremophila has existed isolated in Australia for a very long time while undergoing evolution, and it has had to develop bioactive natural compounds to protect itself from solar radiation, drought and herbivores and to attract pollinating insects. Plants also have to fight bacteria and fungi or evolve symbiotic relationships with them. Altogether, Eremophila constitutes a unique and very diverse and complex treasure trove of compounds that may contribute to or inspire the development of new drugs. We have only just scratched the surface of Eremophila, and I have never found so many new and structurally unique bioactive natural compounds before. So there is a lot of exciting work ahead – and who knows, maybe the next pharmaceutical breakthrough will be found in the Australian desert,” concludes Dan Stærk.

Isolation and structure elucidation of caryophyllane sesquiterpenoids from leaves of Eremophila spathulata” has been published in Phytochemistry Letters. In 2016, the Novo Nordisk Foundation awarded Birger Lindberg Møller and Dan Stærk an Interdisciplinary Synergy Programme grant from the Novo Nordisk Foundation for the project Desert-loving Therapeutics.

Professor Dan Staerk is heading the Natural Products Research group and Copenhagen Small-Molecule NMR Center. His research interests include discovery...

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