Target Selectivity of Cysteine Protease Inhibitors: A Strategy toAddress Neglected Tropical Diseases

Neglected tropical diseases (NTDs) are a group of infectious diseases that mainly affect the population living in poverty and without basic sanitation, causing severe damage to countries' economies. Among them, Leishmaniasis, Chagas disease, sleeping sickness, and related diseases such as Malaria stand out, which, despite being well known, have limited treatments based on old drugs and have high rates of parasite resistance. In addition, current drugs have an uncertain mechanism of action, and there is a need to identify new mechanisms to overcome problems related to side effects and resistance. In a sense, exploring cysteine proteases (CPs) may be a promising alternative that can lead to discovering innovative drugs that may be useful against these diseases. However, exploring CPs in drug discovery should be a cautious and rational process since parasitic CPs show a high degree of homology with human CPs, raising the need to identify increasingly specific patterns of target selectivity to identify safer drugs with fewer side effects. Finally, in this review, we present the main aspects related to the design of CP inhibitor drugs, highlighting structural features of ligands and targets that can be used in the design of new compounds against Leishmaniasis (LmCPB), Chagas disease (Cruzain), sleeping sickness (rhodesain) and malaria (falcipain). We hope our findings can guide researchers in searching for an innovative drug that can be used against these diseases that threaten the world population's health.