Falcipains: Biochemistry, target validation and structure-activity relationship studies of inhibitors as...

Malaria is a tropical disease with significant morbidity and mortality burden caused by Plasmodium species in Africa, the Middle East, Asia, and South America. Pathogenic Plasmodium species have lately become increasingly resistant to approved chemotherapeutics and combination therapies. Therefore, there is an emergent need for identifying new druggable targets and novel chemical classes against the parasite. Falcipains, cysteine proteases required for heme metabolism in the erythrocytic stage, have emerged as promising drug targets against Plasmodium species that infect humans. This perspective discusses the biology, biochemistry, structural features, and genetics of falcipains. The efforts to identify selective or dual inhibitors and their structure-activity relationships are reviewed to give a perspective on the design of novel compounds targeting falcipains for antimalarial activity evaluating reasons for hits and misses for this important target.