Dr Jeremy Burrows, Head of Drug Discovery, reflects on recent progress and partnerships in drug discovery at MMV.
1. How have MMV’s discovery activities evolved over the past year?
In 2018, we continued to focus our discovery efforts on delivering a steady stream of new preclinical candidates. However, through the use of novel platforms – such as Plasmodium liver and gametocyte in vitro assays, in vivo SCID and FRG mouse models and human volunteer infection studies (VIS)– we are now developing a much deeper understanding of the potential of new series and targets. This has allowed us to identify new compound series active beyond the blood stage of the parasite lifecycle and optimize them for clinical development. As such, the range of profiles displayed by preclinical candidates is evolving.
2. Can you tell us about new screening collaborations?
MMV is a founder member of MaLDA – the malaria drug accelerator, a network of academic and industry labs funded by the Bill & Melinda Gates Foundation, and led by Prof. Elizabeth Winzeler at University of California, San Diego. Through research involving resistance selection, genomic1 analysis and editing, metabolomics,2 proteomics,3 conditional gene knockdowns4 and full malaria lifecycle fingerprinting,5 MaLDA is helping us to identify new drug targets and mechanisms of action for confirmed antimalarial compounds identified from screening. In 2018, we worked very closely with MaLDA, supplying compounds, prioritizing biological targets and discussing key MMV portfolio projects. Ultimately, we hope that collaborations with MaLDA and MMV’s partners will bring about a renaissance in target-based drug discovery. This would be significant, as knowing what the biological targets are gives us a real advantage for compound optimization, as per MMV’s Project of the Year 2018.
3. What are the key lessons learned from 2018?
We continue to learn from the successes and failures of different projects. As more and more candidates are delivered, we develop a greater understanding of the potential risks and liabilities of different compound series. One recent example is SJ733, a compound that in 2018 was found to have lower concentrations in humans than expected. Although no longer in MMV’s portfolio, our experience with SJ733 has informed the development of a back-up series by a project team led by Prof. Kip Guy at the University of Kentucky, which, crucially, aims to circumvent the liability identified in SJ733. As such, the “failure” of SJ733, viewed from a different perspective, will hopefully catalyse the success of a back-up.
1. Genomics: a field of genetic research focused on analysis of an organism’s genome (i.e. the entire DNA content present in an organism’s cell).
2. Metabolomics: the study of the small molecule metabolic products of a biological system.
3. Proteomics: the study of the functions, structures and interactions of proteins.
4. Conditional gene knockdown: a technique used to eliminate a specific gene in a certain tissue to study the role of individual genes in living organisms.
5. Malaria lifecycle fingerprinting: understanding the activity of a compound against each stage of the parasite lifecycle.