The impact of phenotypic- versus target-based approaches in antimalarial drug discovery in the last two decades...

Malaria causes major mortality, with the downward trend in the number of cases and deaths seemingly stalled. In 2023, 95% of global malaria deaths were reported in the World Health Organization (WHO) African region, with children under the age of 5 years being the most affected. Artemisinin-combination therapies (ACTs), the currently recommended first-line treatments, are threatened by resistance, which has so far been reported in Africa and Southeast Asia. Thus, new drugs are needed.

In this review, we discuss the two main antimalarial drug discovery paradigms (phenotypic- and target-based drug discovery approaches) and highlight their impact in antimalarial drug development, as judged by the clinical candidates these two drug development philosophies have delivered in the last two decades. We also highlight the geographical imbalance in contributions to research and development (R&D) efforts that led to the development of these clinical candidates.

While phenotypic-based drug discovery outperformed the target-based approach, we propose some strategies to improve chances of success in the latter strategy. Furthermore, although antimalarial drug discovery and development has seen an encouraging shift toward more collaborations among industry, academia, and product development partners, R&D in this space remains concentrated in the global north.