As our 20th anniversary nears, two MMV drug discovery scientists discuss advancements that have been made and the challenges that lie ahead in the discovery of antimalarial medicines.
1. What do you see as the biggest accomplishment in antimalarial drug discovery at MMV within the past 20 years?
DL: The production of a strong and diverse pipeline of chemical series that has led to 22 preclinical candidates targeting unmet medical needs, such as compounds that are active against drug resistant strains, compounds with long duration of action to reduce the complexity and frequency of administration for treatment or chemoprophylaxis, and with safety profiles that will support use in vulnerable groups like children and potentially pregnant women.
BC: Research on relapsing malaria has lagged behind that of acute malaria, due in part to the lack of reliable in vitro liver stage assays for testing of large compound libraries. Over the past few years MMV has been actively working with its partners and the Bill & Melinda Gates foundation to fill this gap, and impressive progress has been made, resulting in new assays and the identification of some potential “hits” or starting points.
2. How has this been achieved?
DL: MMV has strongly supported the development and validation of more than 30 assays and models covering the entire lifecycle of the deadly malaria parasite. Our innovative Product Development Partnership (PDP) model has allowed us to partner with experts in medicinal chemistry and institutions specializing in parasitology and in vivo pharmacology, without whom these assays, models and in turn candidates could not have been brought forward.
BC: Dr Jetsumon Sattabongkot Prachumsri and her group at Mahidol University in Thailand became the first to test 30 MMV portfolio compounds in a P. vivax infected in vitro assay in 2016.
Meanwhile, at the University of Georgia in the US, Prof. Dennis Kyle and his group have developed a high throughput P. vivax liver-stage assay using human primary cells. For the first time in the history of P. vivax research, the team has been able to screen a couple of small-scale libraries of chemical entities representing around 30,000 data points.
3. What lies ahead?
DL: Discovering transmission-blocking drug candidates as well as compounds capable of addressing drug resistance and chemoprotection are major objectives that hold the promise of contributing to the global push towards malaria elimination and eradication.
BC: Screening of even larger chemical libraries will continue in the coming years. This will increase our chances of discovering new “hits”, for the radical cure of P. vivax malaria that do not bear potential risk of haemolysis in G6PD deficient patients. This would reduce safety risks in comparison with the 8-aminoquinolines, which are the current standard of care and would represent an essential step in the push towards malaria elimination in countries in the South American and Southeast Asian regions where P. vivax is responsible for the majority of malaria cases.