RESUMO
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.
Assuntos
Cisteína Proteases/química , Inibidores de Proteases/química , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/química , Trypanosoma/enzimologia , Cisteína Proteases/metabolismo , Humanos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Proteínas de Protozoários/metabolismo , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma/efeitos dos fármacos , Tripanossomíase/tratamento farmacológico , Tripanossomíase/parasitologiaRESUMO
This study examined the process of membrane fusion of yolk granules (YGs) during early embryogenesis of Rhodnius prolixus. We show that eggs collected at days 0 and 3 after oviposition contain different populations of YGs, for example day-3 eggs are enriched in large YGs (LYGs). Day-3 eggs also contain the highest free [Ca(2+)] during early embryogenesis of this insect. In vitro incubations of day-0 YGs with [Ca(2+)] similar to those found in day-3 eggs resulted in the formation of LYGs, as observed in vivo. Fractionation of LYGs and small YGs (SYGs) and their subsequent incubation with the fluorescent membrane marker PKH67 showed a calcium-dependent transference of fluorescence from SYGs to LYGs, possibly as the result of membrane fusion. Acid phosphatase and H(+)-PPase activities were remarkably increased in day-3 LYGs and in calcium-treated day-0 LYGs. Both fractions were found to contain vitellins as major components, and incubation of YGs with calcium induced yolk proteolysis in vitro. Altogether, our results suggest that calcium-induced membrane fusion events take part in yolk degradation, leading to the assembly of the yolk mobilization machinery.