Falcipain-2 and Falcipain-3 Inhibitors as Promising Antimalarial Agents

Malaria remains a serious problem in global public health, particularly widespread in South America and in tropical regions of Africa and Asia. Chemotherapy is actually the only way to treat this poverty-related disease, since an effective vaccine is not currently available. However, the onset of resistance to the most common antimalarial drugs sometimes makes the current therapeutic regimen problematic. Therefore, the identification of new targets for a new drug discovery process is an urgent priority. In this context, falcipain-2 and falcipain- 3 of P. falciparum represent the key enzymes in the life-cycle of the parasite. Both falcipain- 2 and falcipain-3 are involved in hemoglobin hydrolysis, an essential pathway to provide free amino acids for the parasite metabolic needs. In addition, falcipain-2 is involved in cleaving ankirin and band 4.1 protein, which are cytoskeletal elements essential for the stability of the red cell membrane. This review article is focused on the most recent and effective inhibitors of falcipain-2 and falcipain-3, with particular attention to peptide, peptidomimetic or nonpeptide inhibitors, which targeted one or both the malarial cysteine proteases, endowed with a consistent activity against P. falciparum.