In the modern era of increased air travel and densely concentrated, interconnected populations, the world is more vulnerable to pandemic diseases than ever before, as seen by the recent and ongoing outbreaks of COVID-19, Ebola, Zika, chikungunya, dengue fever, Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS) and influenza. Now more than ever, new and innovative approaches are urgently needed to mobilize the potential for discovering new drugs to fight global health emergencies. Under its ethos of ‘openness’, MMV has pioneered several drug discovery initiatives to support R&D efforts in malaria and other neglected tropical diseases.
Open-access libraries, such as the Malaria Box, Pathogen Box, Stasis Box, Pandemic Response Box and larger compound collections have catalysed drug discovery research across the globe. These libraries contain drug-like compounds that researchers can use to screen against neglected or pandemic diseases. So far, around 700 of these open-access libraries have been distributed worldwide free of charge, and findings from them have led to over 110 publications, adding significantly to the global scientific knowledge base.
Prof. Lyn-Marie Birkholtz tells us more about her research experience with the Pandemic Response Box.
What made you want to request the Pandemic Response Box?
The Pandemic Response Box is a really exciting tool for a researcher, as it contains compounds with antiviral, antibacterial and antifungal properties. This allows us to identify entirely new targets that we might not otherwise identify from screening only antimalarial compound libraries, with the aim of repurposing these new targets against malaria.
Have you had any success in identifying hits so far?
We have identified a number of hits. Some of them target all stages of the parasite life cycle (we call these ‘pan-reactive hits’), while others appear to target one or more specific stages. We are particularly excited about the stage-specific hits as we have found activity against both the asexual and sexual (gametocyte) blood stages of the life cycle. Targeting gametocytes, the reproductive form of the malaria parasite, would allow us to prevent transmission of parasites back into the mosquito during its next blood meal, effectively breaking the parasite’s life cycle and preventing another cycle of reinfection.
How are you collaborating with the MaLaria Drug Accelerator (MaLDA)?
As part of our testing, we are trying to profile the mechanisms of action of the hits we have identified from the Pandemic Response Box. Some of these compounds already have very well characterized mechanisms of action in other diseases, which certainly helps to focus our research, but other compounds don’t. MaLDA, a network of academic and industry partners,1 gives us access to drug discovery techniques and resistance screening tools that enable us to profile these compounds much quicker.
In the wider context of malaria eradication, how important is drug discovery in terms of identifying and bringing forward next-generation antimalarial compounds?
We have learnt from the past that we cannot rely on a single approach to achieve eradication. Continued efforts are needed to develop next-generation drugs that not only treat symptomatic patients but can also eliminate the parasite reservoir of asymptomatic patients. We must remain innovative and explore new chemical and biological targets, as well as develop tools to assess and predict the efficacy of compounds as early as possible in the development process.
What has it been like working with MMV?
It has been extraordinary. With MMV’s support, we have been able to accelerate the progress of our discovery initiatives. In South Africa, we have a proud record in antimalarial drug discovery, having brought forward MMV048 with another of MMV’s partners, Prof. Kelly Chibale at the University of Cape Town. It is collaborations like these that have allowed us to come so far, so quickly, in antimalarial drug discovery
1. A network of 13 academic and industry partners focused on identifying new antimalarial drug targets and unravelling the mechanisms by which confirmed antimalarial compounds work.