Taking aim at malaria: a target-based approach to drug design
At present, there are relatively few validated targets in the malaria parasite. The discovery and validation of PfKRS1 as a novel biological target is therefore an important and exciting development and the researchers involved have been awarded MMV's 2018 Project of the Year.
Representatives from the team tell us more: Dr Beatriz Baragaña, Drug Discovery Unit (DDU), University of Dundee, UK; Prof Ian Gilbert, DDU, Dundee, UK; Paul Willis, Senior Director, Drug Discovery, MMV; Prof Kevin Read, DDU, University of Dundee, UK; Delphine Baud, Project Coordinator, Drug Discovery, MMV.
1. What is the role of PfKRS1 in the malaria parasite? What makes it a good drug target?
BB: KRS1 is a key enzyme involved in protein synthesis. Without it, the parasite cannot grow and therefore cannot survive. Unusually, PfKRS1 is present across all stages of the parasite lifecycle – both asexual and sexual blood stages, as well as the liver stage – making it an attractive biological target that can address multiple target candidate profiles. KRS1 is also present in other pathogens, such as the parasite that causes cryptosporidiosis. Compounds active against PfKRS1 therefore have the potential to treat not only malaria, but also other neglected tropical diseases.
2. How was PfKRS1 discovered and validated?
IG: The discovery and validation of PfKRS1 speaks to the power of collaboration in malaria research. The first step was the discovery of a natural product (cladosporin) active against the malaria parasite, and the subsequent identification of its target (PfKRS1) by Prof. Elizabeth Winzeler, one of MMV’s long-term collaborators at the University of California San Diego.2 Cladosporin was not developable as a drug candidate; however, working through the Structureguided Drug Discovery Coalition, funded by the Bill & Melinda Gates Foundation, we carried out a project with the specific aim of exploring the potential of PfKRS1 as a novel therapeutic target.
Working in collaboration with Prof. Wes van Voorhis at the University of Washington, we identified an inhibitor from a compound screen against PfKRS1. This led to the screening of further compound libraries, generating more chemical series for optimization at DDU. We were also able to validate PfKRS1 as a drug target in the SCID model of malaria3,4 – the first time an animal model has been used to validate this target in the malaria parasite.
3. Structure-based drug design was also used in this project. Why was this important?
PW: Traditionally, the malaria drug discovery community has relied primarily on phenotypic screening to identify new compounds, but since this approach lacks an understanding of how the compound works in humans, it can make the optimization of a series to deliver a drug candidate more challenging. Structure-based drug design is a more sophisticated (though less commonly used) technique that allows scientists to use 3D computational models to visualize how specific compounds interact with their biological target. On this project, the insights gained from structure-based drug design have enabled us to optimize the potency and selectivity5 of compounds active against PfKRS1.
4. How has team collaboration contributed to the success of this project?
KR: The team synergy has been fantastic. MMV and DDU have enjoyed a successful working relationship for almost 10 years now, starting in 2010/11 with a project that ultimately led to the delivery of a new drug candidate, M5717 – currently in Phase I testing. MMV has an in-depth understanding of malaria and an extensive network of global collaborators, which really helps to move compounds along the discovery pathway. At all stages, DDU has benefited enormously from MMV’s advice and mentorship.
DB: Team collaboration has played a fundamental role in the success of this project. Testing new compound series is a logistically complex process as the validated assays for studying different stages of the parasite lifecycle are based all over the world. Without the strong partnerships we have with a wide range of centres – such as Imperial College (London, UK) and TropIQ (the Netherlands) for transmission-blocking assays; DDU (Dundee, UK) and GSK (Tres Cantos, Spain) for asexual blood-stage testing; and centres in Cambodia, Thailand and the USA for liver-stage testing – this work would simply not be possible.
5. How does it feel to receive MMV’s Project of the Year award?
BB: It’s a great endorsement for the team. The drug discovery pathway is a long one, and we first started working on this project back in 2014. This award recognizes the consistently hard work of the project team and its collaborators, and also motivates us to keep pushing forward. We are particularly proud given the many other competitive drug discovery projects currently active in MMV’s portfolio.
6. What are the next steps for this project?
DB: Our focus now is on improving the properties of the compound series to deliver a drug candidate that can pass all the safety milestones required to advance to clinical development. Because PfKRS1 is an enzyme essential for protein synthesis, we know that if we can successfully develop a drug candidate, it could kill the parasite at several different stages in the lifecycle, giving rise to a compound with good therapeutic potential for malaria. Going forward, we will continue to ensure that the goals of the project align with MMV’s target candidate profiles and strategic imperatives, as well as the global elimination and eradication agenda for malaria.
1. van Montfort R & Workman P., Essays in Biochemistry 61:431-437 (2017)
2. Cladosporin was discovered in a phenotypic screen carried out by the Novartis Institute for Tropical Diseases in collaboration with the Genomics Institute of the Novartis Research Foundation.
3. Baragaña B et al. “Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis”. PNAS. 116(14):7015–7020 (2019)
4. SCID model: the laboratory model of malaria that provides the most accurate prediction of drug response in humans.
5. Selective activity against enzymes in the malaria parasite, without any cross-reactivity to the equivalent human enzymes.
Dr Beatriz Baragaña, Prof. Ian Gilbert, Paul Willis, Prof. Kevin Read, Delphine Baud