The pharmacological potential of natural products

Brazilian researcher who heads a lab in the United States explains how biosynthesis of natural compounds is enabling innovation in drug development and production.

By José Tadeu Arantes  |  Agência FAPESP – Almost half and half: this is how medical drugs are divided in terms of the sources of their active principles. Of the total available in the marketplace, 49.6% are synthetic compounds, mostly made from petroleum products, and 50.4% come from natural products and derivatives. The phrase “natural products and derivatives”, used broadly here, refers to molecules produced by plants, fungi, bacteria and other organisms, or molecules based on artificially modified versions of these precursors.

This information was offered by Alessandra Estáquio, a professor at the University of Illinois at Chicago (UIC), during the Second Workshop on Recent Advances in the Chemistry of Natural Products, hosted by the FAPESP Research Program on Biodiversity Characterization, Conservation, Restoration and Sustainable Use (BIOTA-FAPESP) at FAPESP’s auditorium on November 9, 2017.

“In developing medical drugs, it’s important to use both synthetic and natural sources. Each has its advantages and drawbacks. One advantage of natural products is that their biological activity is the result of millions of years of evolution. Another is that their production is more sustainable,” Eustáquio told Agência FAPESP. 

As noted by another participant in the workshop, Sarah O’Connor, Professor and Project Leader in Biological Chemistry at the John Innes Center, Norwich, UK, medicinal use of plants dates from the Paleolithic Period. Thanks to the possibility of modifying the chemical structure of molecules to boost their pharmacodynamic properties, research in natural products and derivatives is now a highly promising field.

Morphine (a painkiller), erythromycin (an antibiotic), cyclosporine (an immunosuppressant) and artemisinin (an anti-malaria drug) are only a few such substances that are widely used in medicine.

“In some cases, the structure found in nature is used directly as medication,” Eustáquio said. “An example is paclitaxel, an anti-cancer chemotherapy drug derived from the bark of the Pacific yew tree (Taxus brevifolia). However, most natural compounds require modification of some kind in order to function as medication. Some have to be stabilized because they degrade very quickly. Others need alterations that favor their absorption and distribution in the human organism. Yet others need to have their effect boosted, and so on.” 

Even in the case of paclitaxel, on average, 3,000 trees are needed to obtain one kilogram. Hence the role of semi-synthesis or plant cell culture in order for medical drugs based on natural products to be manufactured on a commercial scale. 

“Various kinds of intervention are possible,” Eustáqio said. “One is semi-synthesis, which consists of isolating the molecule of interest and modifying it partially by means of chemical processes. Another is reproduction of the complete structure using synthesis. A third, more recent, type of intervention consists of using genetic engineering to modify the organisms that produce the compounds. In some cases, genetic engineering involves transferring the genes responsible for the compound from one organism to another – from a plant to a bacterium or yeast, for example. The advantage of this is that bacteria and yeasts are easier and faster to grow than plants. For example, a US group led by Jay Keasling at the University of California, Berkeley, managed to transfer artemisinin precursors to yeast.” 

The group led by Eustáqio at UIC works with bacteria to develop antibiotics and anti-cancer compounds. “Our main aim is to understand how bacteria synthesize molecules that can be used as antibiotics and especially which genes are involved. This knowledge, in turn, can be used to have bacteria produce larger amounts of the compounds or to modify the molecules so that they become more effective drugs. It’s basic research, but with applications in mind,” she said.

“The microbial genome sequencing boom has shown that microorganisms’ potential biosynthetic capacity is far greater than anyone imagined. A typical bacterium to which only a few compounds are attributed could produce more than 30 in light of its genomic structure. It so happens that most of the genes responsible for biosynthesis are silenced or not well expressed in laboratory growth conditions. Once we know which genes they are and what their potential is, we can activate them and obtain the corresponding compounds.”

According to Eustáqio, the ability to predict the biosynthetic potential of microorganisms from their genomes (“genes to molecules”) and knowing which genes code for the biosynthesis of a specific natural product (“molecules to genes”) could lead to major innovations in drug development.

Speaking to Agência FAPESP about the workshop, Roberto Berlinck, Full Professor at the University of São Paulo’s São Carlos Chemistry Institute (IQSC-USP), said part of the event’s significance was that it had brought researchers from the US and UK to discuss their work with colleagues in Brazil.

“They’re doing research at the frontier of knowledge on the metabolism of plants and microorganisms to understand how molecules of interest are formed and how they can be used to improve the quality of life, since these compounds are key ingredients not just of novel drugs for both humans and animals but also of products for biological control in agriculture, replacing herbicides, pesticides and so on,” Berlinck said.