Abstract
The trypanosomatids Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp. cause Chagas disease, leishmaniasis and human African trypanosomiasis, respectively. It is estimated that over 10 million people worldwide suffer from these neglected diseases, posing enormous social and economic problems in endemic areas. There are no vaccines to prevent these infections and chemotherapies are not adequate. This picture indicates that new chemotherapeutic agents must be developed to treat these illnesses. For this purpose, understanding the biology of the pathogenic trypanosomatid-host cell interface is fundamental for molecular and functional characterization of virulence factors that may be used as targets for the development of inhibitors to be used for effective chemotherapy. In this context, it is well known that proteases have crucial functions for both metabolism and infectivity of pathogens and are thus potential drug targets. In this regard, prolyl oligopeptidase and oligopeptidase B, both members of the S9 serine protease family, have been shown to play important roles in the interactions of pathogenic protozoa with their mammalian hosts and may thus be considered targets for drug design. This review aims to discuss structural and functional properties of these intriguing enzymes and their potential as targets for the development of drugs against Chagas disease, leishmaniasis and African trypanosomiasis.
Highlights
Severe diseases caused by pathogenic microorganisms affect millions of humans and animals around the world and have been a constant challenge
It is estimated that more than 10 million people worldwide have Chagas disease, leishmaniasis or human African trypanosomiasis (HAT) with 600 million people being at risk to be infected in the poor areas where those illnesses are
Prolyl oligopeptidase is an S9 serine protease family consisting of the prototype prolyl oligopeptidase (POP, EC 3.4.21.26), oligopeptidase B (OPB, EC 3.4.21.83), dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5), acylaminoacyl peptidase (ACPH, EC 3.4.19.1) and glutamyl endopeptidase C (GEP, EC 3.4.21.19) (Fig. 1) [7]
Summary
Severe diseases caused by pathogenic microorganisms affect millions of humans and animals around the world and have been a constant challenge. Chagas disease, leishmaniasis and human African trypanosomiasis (HAT) result from infections by the trypanosomatids Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites are unicellular eukaryotic protozoa belonging to the order Kinetoplastida. HAT is the cause of more than 50,000 deaths annually [2] This scenario requires the development of new molecules aiming at both prevention and control of these intriguing parasite infections. For this purpose, understanding the biology of trypanosomatid parasites, as well as their interactions with hosts, is a fundamental step in this direction. The purpose of this article is to review the structural and functional properties of prolyl oligopeptidase and oligopeptidase B of T. cruzi, Leishmania major and T. brucei in parasite-host interactions and to discuss their potential as targets for selective inhibitors
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