Discovering new target space for the development of drugs against malaria parasites.

Infectious diseases are a continuous threat for Singapore and the region. While Singapore is considered malaria-free there are regular cases of imported cases seen in Singapore hospitals. The appearance of multidrug resistant malaria poses a threat to Singapore as well, as it increases the likelihood of treatment failure and at the same time increases the risk of spread within the country. The threat that multidrug resistant malaria poses for the world is even greater and it is not unlikely that it would lead to a doubling of malaria deaths each year. This risk has now been further increased due to the significant disruption of health care provisions as a result of the COVID pandemic. The complex and unique biology of the malaria parasite offers new druggable targets that have so far not been explored at the same time our understanding of targets and mode of action of many antimalarials remains limited. We have recently adapted Cellular Thermal Shift Assay (CETSA) to directly identify the intracellular targets of a number of established antimalarial drugs. At the same time we have identified a range of highly promising new chemical scaffolds with strong activity against malaria parasites. The combination of new compounds with attractive therapeutic properties along with the CETSA and other -omic approaches as well as strong medicinal chemistry support provides us with a novel and powerful strategy to survey the potential target space for new antimalarial compounds. The primary aim of this proposal is therefore to leverage on these already developed capacities to rapidly supply the antimalarial development pipeline with unique and clinically-suitable chemical scaffolds which exert their activity on novel cellular pathways to combat drug-resistant parasites in the field. Importantly, the know-how and expertise developed here in would put Singapore into a unique position to become an important player in the development of new anti-infective’s.