Targeting the active sites of malarial proteases for antimalarial drug discovery: approaches, progress and challenges

- Drug-resistant malaria represents a serious global threat to malaria control.
- Targeting malarial proteases led to discovery of several promising molecules, but none has yet become a clinical candidate.
- Falcilysin, DPAP1 and PfM1-AAP are less explored validated targets.
- Challenges in protease-based drug discovery are specificity, pharmacokinetics, drug stability and functional redundancy.
- There is still hope to develop next-generation antimalarial drugs targeting malarial proteases.

Malaria is an infectious disease causing vast mortality and morbidity worldwide. Although antimalarial drugs are effective in several parts of the world, there is a serious threat to malaria control as malaria parasites are continuously developing widespread resistance against currently available antimalarial drugs, including artemisinin. Such widespread antimalarial drug resistance confirms the need to improve the efficacy of existing or new drugs as well as to develop alternative treatments through the identification of novel drug targets and the development of candidate drugs. Similar to proteases in other parasitic diseases such as leishmaniasis, schistosomiasis, Chagas disease and African sleeping sickness, malarial proteases constitute the major virulence factors in malaria. Malarial proteases belong to several classes and many of them have been targeted for the design and discovery of antimalarial agents. This review summarises the approaches, progress and challenges in the design of small-molecule inhibitors as antimalarial drugs targeting the inhibition of various malarial proteases.