Cysteine peptidase inhibitors in trypanosomatid parasites

Parasitic diseases caused by pathogenic protozoa remain a challenge for public health. Despite efforts to control transmission, to improve early diagnosis and to optimize patient care, millions of infected people, mainly in poor areas of the globe, develop debilitating pathologies that are often fatal. For most of those disorders, the current treatments are greatly unsatisfactory and the continuous search for alternative chemotherapies remains at the center of research. Over the last decades, cysteine peptidases of protozoa feature as highly promising drug targets and their validation in laboratory models of disease or experimental infections instigated growing efforts in medicinal chemistry, aiming at the development of compounds with therapeutical potential. More recently, it was uncovered that protozoa also express new families of endogenous proteinaceous peptidase inhibitors that act as potential virulence factors. In this review, we will cover the main findings that contributed to the validation of cysteine peptidases from Trypanosoma cruzi, Trypanosoma brucei and Leishmania as drug targets and the current knowledge of their biological roles in those organisms. We give an overview of the development of small molecule cysteine peptidase inhibitors with anti-parasite activity and describe the current background on natural peptidase inhibitors in trypanosomatids.