Cysteine proteases are essential hydrolytic enzymes present in the majority of
organisms, including viruses and unicellular parasites. Despite the high sequence identity
displayed among these proteins, specific structural features across different species grant
distinct functions to these biomolecules, frequently related to pathological conditions.
Consequently, their relevance as promising targets for potential specific inhibitors has
been highlighted and occasionally validated in recent decades. In this review, we discuss
the recent outcomes of structure-based campaigns aiming the discovery of new inhibitor
prototypes against cruzain and falcipain, as alternative therapeutic tools for Chagas disease
and malaria treatments, respectively. Computational and synthetic approaches have
been combined on hit optimization strategies and are also discussed herein. These rationales
are extended to additional tropical infectious and neglected pathologies, such as
schistosomiasis, leishmaniasis and babesiosis, and also to Alzheimer’s Disease, a widespread
neurodegenerative disease poorly managed by currently available drugs and recently
linked to particular physiopathological roles of human cysteine proteases.