Plasmodium falciparum proteases as new drug targets with special focus on metalloproteases

Malaria poses a significant global health threat particularly due to the prevalence of Plasmodium falciparum infection. With the emergence of parasite resistance to existing drugs including the recently discovered artemisinin, ongoing research seeks novel therapeutic avenues within the malaria parasite. Proteases are promising drug targets due to their essential roles in parasite biology, including hemoglobin digestion, merozoite invasion, and egress. While exploring the genomic landscape of Plasmodium falciparum, it has been revealed that there are 92 predicted proteases, with only approximately 14 of them having been characterized. These proteases are further distributed among 26 families grouped into five clans: aspartic proteases, cysteine proteases, metalloproteases, serine proteases, and threonine proteases. Focus on metalloprotease class shows further role in organelle processing for mitochondria and apicoplasts suggesting the potential of metalloproteases as viable drug targets. Holistic understanding of the parasite intricate life cycle and identification of potential drug targets are essential for developing effective therapeutic strategies against malaria and mitigating its devastating global impact. •This review article contains updated critical analysis of proteases and their vital roles in the survival of malaria parasite Plasmodium falciparum.•The proteases of the RBC cycle inside human hosts is taken for the critical review owing to their crucial roles and potential drug targets.•The review emphasizes on proteases as drug targets giving focus on metalloproteases as this class is implicated to have crucial roles and are poorly characterized.•The review highlights the inhibition of parasite growth using inhibitors against crucial proteases and metalloproteases to be specific. The information in this review provides updated information for development of anti-malarial drugs.