Introduction and Background of the Project

1.Introduction

Fragment-based screening for hit generation has yet to be applied to malaria drug discovery, despite having delivered high quality series for further optimization in numerous therapeutic areas. The deployment of innovative techniques in malaria R&D will maximize the chances of delivering novel drugs to counter the threat of emerging resistance to existing therapies. We have therefore assembled a multinational team of experts in fragment-based screening hit generation who will apply this powerful technique against two high priority malaria drug targets.

2.Project objective

The goal of the project is to generate high quality hit compound series against two highly validated malarial targets, by applying, for the first time, the state-of-the-art XChem fragment approach of X-ray structure-accelerated, synthesis-aligned lead discovery. The targets, Pf DPCK and Pf KRS are essential, novel Plasmodium targets prioritized by the malaria drug discovery community. There is a need for high quality chemical matter to serve as starting points for further optimisation.

3.Project design

Crystallization conditions on the two selected biological targets will be optimised to enable large-scale production of protein crystals (~1000) that consistently diffract to a high resolution (preferably < 2.5 Å). Each crystal will then be soaked separately with a fragment from a library that was optimised to cover chemical space and designed to allow rapid, cheap follow-up synthesis to provide quick structure activity data. Solving the crystal structure of fragments that bind to the target gives an understanding of how that compound binds to the target and allows the team to then apply AI and medicinal chemistry techniques to design, then synthesize new compounds that will bind more tightly to the target. Through application of these design-make-test cycles the team will optimize the selected hits to deliver high quality drug discovery starting points. A suite of biochemical and biophysical tools will be used to characterize the hit compounds, with advanced compounds being fully profiled for malaria lifecycle activity.

How can your partnership (project) address global health challenges?

Malaria caused approximately 627,00 deaths in 2020, mostly in children under five years of age and pregnant women. This was a significant increase in cases compared to preceding years primarily due to disruptions in access to diagnosis and treatment resources because of the COVID-19 global pandemic.
Artemisinin combination therapies (ACTs) are the mainstay frontline treatment of malaria. Curtailing the effectiveness of ACTs is the emergence of resistance in Southeast Asia and recently in Sub-Saharan Africa, If resistance becomes widespread in Africa (where most deaths occur), a major health crisis is possible, highlighting the need for new therapies, ideally with novel mechanisms to be approved for use. In response to this crisis scenario and with the eventual aim of eradicating the disease, MMV seeks to discover, develop, and deliver new drugs with novel modes of action which address resistance risks associated with existing therapeutics. Development of compounds which can block transmission and be used in chemoprotection/chemoprevention settings, in addition to acute treatment, would be especially valuable to drive the eradication agenda.

What sort of innovation are you bringing in your project?

The application of fragment-based screening and optimization to malaria drug discovery is novel.  The team will deliver new starting points for drug discovery against high value malaria targets for which there are currently no drug candidates, using innovative AI optimization techniques.

Role and Responsibility of Each Partner

The group at University of Oxford is responsible for producing and crystallizing both targets, then carrying out the fragment screens and initial fragment optimization. The groups at University of Dundee and University of Tokyo will carry out detailed biochemical characterization of compounds.  The University of Dundee will lead the optimization of the prioritized hits, through the application of AI-driven techniques to deliver validated hits, suitable for progression to lead optimization. MMV will provide malaria drug discovery expertise and full profiling of the hits for malaria life cycle activity.