Inhibition of cysteine proteases as targets of antimalarial candidates: A narrative review

Abstract

Malaria is a parasitic disease that is highly prevalent throughout the world. In 2021, it affected 247 million people and caused 619,000 deaths. Its transmission occurs through the bite of a female Anopheles mosquito infected by Plasmodium. Of the species that infect humans, Plasmodium falciparum is the most lethal. One of the main factors that has hampered the control of malaria is the large number of parasites that are resistant to the usual antimalarials, including artemisinin and derivatives. Therefore, it is necessary to discover new drugs that are more effective, and that act on targets that only interfere with the parasite. Given this, the present work aimed to discuss a new perspective of therapeutic approach to the treatment of malaria, with a specific target on P.falciparum. In this way, scientific works published in databases such as: PubMed, Scielo and Google Scholar were analyzed. After analyzing the data found in the literature, it was observed that falcipains (cysteine proteases) are of great importance for maintaining the life cycle of P. falciparum, especially falcipains 2 and 3. These enzymes act in the invasion of erythrocytes, degradation of hemoglobin, and in the proteolytic development of the parasite. Therefore, the inhibition of these enzymes is a good therapeutic target. We also identified that substances that have Michael acceptors in their structure (as is the case of some Morita Baylis Hillman adducts) are capable of inhibiting cysteine proteases, thus being good candidates for antimalarials.