HIV aspartic protease inhibitors as promising compounds against Candida albicans. activity produced by different species of promastigotes with HIV PIs induced several perturbations on the parasite homeostasis, including loss of the motility and arrest of proliferation/growth. The HIV PIs also induced an Nutlin 3b increase in the level of reactive oxygen species and the appearance of irreversible morphological alterations, triggering parasite death pathways such as programed cell death (apoptosis) and uncontrolled autophagy. The blockage of physiological parasite events as well as the induction of death pathways culminated in its incapacity to adhere, survive and escape of phagocytic cells. Collectively, these results support the data showing that parasites treated with HIV PIs have a significant reduction in the ability to cause infection. Similarly, the treatment of Nutlin 3b cells with pepstatin A showed a significant inhibition on both aspartic peptidase activity and growth as well as promoted several and irreversible morphological changes. These studies indicate that aspartic peptidases can be promising targets in trypanosomatid cells and aspartic proteolytic inhibitors can be benefic chemotherapeutic agents against these human pathogenic microorganisms. genus, present in Nutlin 3b tropical and subtropical regions of the world (Fig. ?22) [3, 7-12]. Infections in humans occur primarily through blood-sucking insects, such as triatomines, in the case of and different phlebotomine sand flies species for the genus [7-12]. The spread of these diseases all over the world, to many developed, non-endemic countries, is related to the globalization process and the movement of unknowingly infected people (Fig. ?22). Open in a separate window Fig. (2) Geographic distribution of cases reported for African trypanosomiasis, Chagas disease and leishmaniasis around the world. Data collected from the WHO web site (http://www.who.int/en). Table 1. Diseases Caused by Trypanosomatids of Human Medical Importance and roughly 100 million were at risk of the disease worldwide, mostly but not restricted to Latin America. It was estimated that more than 10,000 individuals died of Chagas disease in 2008. For leishmaniasis, in 2010 2010, 350 million people were considered at risk of contracting the disease, and about 2 million cases occur annually, of which 0.5 million correspond to visceral leishmaniasis (Table ?11 and Fig. ?22) . Although affecting many people around the world, the major diseases caused by parasites from the Trypanosomatidae family have no Rabbit polyclonal to Complement C4 beta chain efficient treatment or vaccination. The available drugs (Table ?11) are expensive, toxic and many parasites have already developed resistance to the chemotherapy, resulting in an urgent need to identify new targets for therapeutic alternatives [7, 8, 11, 14-16]. In this sense, this review will describe the current knowledge on trypanosomatids aspartic peptidases and their inhibitors, since there is substantial data indicating that they can be a promising target for chemotherapy. 2. ?PEPTIDASES Peptidases, proteinases or proteases are enzymes that catalyze the hydrolysis of peptide bonds or, Nutlin 3b in other words, proteins able to hydrolyze other proteins or peptides. These enzymes were initially classified into exopeptidases or endopeptidases according to the reaction catalyzed. Exopeptidases are capable of hydrolyzing peptide bonds at the ends of a polypeptide chain, releasing single amino acid, dipeptide or tripeptide residues, while endopeptidases preferentially act on peptide bonds in the inner regions of Nutlin 3b a polypeptide [17, 18]. The availability of structural and mechanistic information on these enzymes led to improvements on the classification schemes. According to the nature of the catalytic site, peptidases can be classified as aspartic, cysteine, metallo, serine, threonine, glutamic and asparagine type [17-19]. The intensive research on peptidases generates a wide amount of information, requiring a system of classification for the comprehensive study of this diversity. Recently, a new method of classification was introduced and can be easily accessed in the MEROPS database server . In this system, peptidases of the different classes can be further grouped into families on the basis of statistically significant similarities in amino acid sequence. For nomenclature, each family is identified by a letter that represents the catalytic domain, where A is used for aspartic type, C for cysteine.