Prior to delivering a workshop at the University of São Paolo (USP) Ribeirão Preto campus, UK Network members Patrick Steel, Paul Denny, Ehmke Pohl and colleagues from USP and Durham University, spent a day exploring. The Serra da Canastra national park in Minas Gerais, the origin of the São Francisco river, is home to a tropical and scrubby forest, known to these scientists as USP professor Noberto Lopes’ “chemical hunting ground”. The workshop, “Development and evaluation of bioactive compounds” (March 25th-29th 2019; funded by Brazil’s Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) ‘SPRINT’ initiative), equipped ~40 Brazilian postgraduate students with skills to source novel chemicals from plants, fungi and animals. USP’s natural products library already holds many naturally-sourced compounds new to science, but more are needed – as leads for new medicines to treat the Neglected Tropical Diseases (NTDs) affecting Brazil and other developing countries. On this hot day, the team veer off a well-trodden path to go exploring in the forest, taking in spectacular waterfalls and an impromptu swim.
A response to the global challenge of NTDs
The NTD Network project, funded by the Global Challenges Research Fund (GCRF), is gathering a worldwide scientific community of diverse expertise to find new solutions for the NTDs leishmaniasis and Chagas disease. These infections affect millions of people worldwide, mostly targeting the poorest of the poor. Although the plight of these patients is distant for most researchers in the UK, this became real for Paul and Ehmke during an NTD Network visit to India in 2018; where many of the Networks’ Asian students have first-hand experience of the devastating impact of leishmaniasis on their families and communities. Similarly, here in Brazil some of the students have witnessed the consequences of the ‘runaway epidemics’ of leishmaniasis, Chagas disease and other NTDs in remote regions across South America. As the term ‘neglected’ suggests, researchers, governments and the pharmaceutical industry need to work together to treat and protect the millions of people at risk.
Potential solutions in the natural world
USP’s Norberto Lopes, a world leader in discovering unique compounds from natural sources, is exploring the pharmacopoeia of novel chemicals available ‘on his doorstep’, in the forests of Minas Gerais. Global pharmaceutical compound libraries contain chemicals with a limited number of scaffolds (molecular ‘skeletons’). While computer modelling can generate many diverse compounds from these scaffolds, nature offers many more. Crucially, unlike the computer-created chemicals, the compounds made by living cells have a biological function; this increases their likelihood of also being pharmacologically active, i.e. useable as new drugs. Indeed, many of our current drugs were developed from compounds found in plant species with a long history of use as natural ‘folk remedies’. Noberto’s team, plus NTD Network members and collaborators in South America and Asia, have created new libraries of compounds from terrestrial and marine sources, but Ehmke emphasises that “…we have barely scratched the surface of what nature can provide!”.
Following the ‘glow’ of natural products
Norberto’s product-hunting expeditions usually span two weeks, and involve searching the forest at night using fluorescent lamps. Ehmke explains; “Fluorescence highlights small, complicated molecules, which are likely to have new and complex scaffolds”. Traditional plant remedies are rich in these molecules, e.g. flavonoids, alkaloids, terpenes, saponins and phenolics, many of which are naturally fluorescent due to aromatic groups (rings of carbon atoms) in their scaffolds. Norberto exploits this property to find new natural sources of these compounds; the team literally look for plants, fungi and animals that “glow in the dark”. This led to the discovery of a fluorescent chromophore in the polka-dot tree frog, Hypsiboas punctatus, the first recorded case of naturally-occurring fluorescence in amphibians.1
Once compounds have been isolated from their source species, the next stage is to screen for those with anti-parasitic activity. Promising leads are further analysed to identify the molecular target in the parasite cell, and unravel the mechanism of action for this potential new drug. An ‘ideal’ compound would target the parasite, would not harm the patient, would be easily soluble (enabling administration in tablet-form), and would be cheap to make.
Since it can take 10 years or more to develop a lead compound into a new drug, the NTD Network project is at the beginning of a long-term endeavour. Network members are therefore concerned to equip today’s young researchers with the sophisticated skills in using biological, chemical, biophysical and structural tools, needed for impactful NTD research. This week, students from USP will gain skills and insights from chemistry, structural biology and parasitology. The team are hoping to inspire this cohort to dedicate their careers to finding solutions for leishmaniasis, Chagas disease and other NTDs. Partnerships with organisations such as FAPESP are vital for supporting the Network to share their skills across a breadth of students in endemic countries, to see this project to completion.
Whilst the NTD Network’s practical training programme is now underway across the global partners, with a further natural products workshop offered in Karachi later this year, Paul and the team are clear that our first priority is finding and validating new drug targets in the parasites that cause leishmaniasis and Chagas disease. They are also aware that this initial step towards developing better treatments for NTDs is likely to require us “straying off the well-trodden path”.
Annabelle Pohl and Mags Leighton
- Taboada C, et al. PNAS 2017; 114(14): 3672-3677.