This article provides a comprehensive review of several subclasses of metallo-type peptidases expressed by the main clinically relevant protozoa, including Plasmodium spp., Toxoplasma gondii, Cryptosporidium spp., Leishmania spp., Trypanosoma spp., Entamoeba histolytica, Giardia duodenalis, and Trichomonas vaginalis. These species comprise a diverse group of unicellular eukaryotic microorganisms responsible for widespread and severe human infections. Metallopeptidases, defined as hydrolases with activity mediated by divalent metal cation, play important roles in the induction and maintenance of parasitic infections. In this context, metallopeptidases can be considered veritable virulence factors in protozoa with direct/indirect participation in several key pathophysiological processes, including adherence, invasion, evasion, excystation, central metabolism, nutrition, growth, proliferation, and differentiation. Indeed, metallopeptidases have become an important and valid target to search for new compounds with chemotherapeutic purposes. The present review aims to gather updates regarding metallopeptidase subclasses, exploring their participation in protozoa virulence as well as investigating the similarity of peptidase sequences through bioinformatics techniques in order to discover clusters of greater relevance for the development of new broad antiparasitic molecules.

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_________________________________________________________________Sumário 4.2 Clonagem do gene da UCP-like a partir do DNA genômico de A. fumigatus........ 4.3 Clonagem da região codificadora da UCPlike de A. fumigatus por RT-PCR........ 4.4 Sequenciamento do gene da UCP-like de A.

Trichomonas vaginalis is responsible for 156 million new cases per year worldwide. When present asymptomatically, the parasite can lead to serious complications, such as development of cervical and prostate cancer. As infection increases the acquisition and transmission of HIV, the control of trichomoniasis represents an important niche for the discovery and development of new antiparasitic molecules. This urogenital parasite synthesizes several molecules that allow the establishment and pathogenesis of infection. Among them, peptidases occupy key roles as virulence factors, and the inhibition of these enzymes has become an important mechanism for modulating pathogenesis. Based on these premises, our group recently reported the potent anti-T. vaginalis action of the metal-based complex [Cu(phendione)3](ClO4)2.4H2O (Cu-phendione). In the present study, we evaluated the influence of Cu-phendione on the modulation of proteolytic activities produced by T. vaginalis by biochemical and molecular approaches. Cu-phendione showed strong inhibitory potential against T. vaginalis peptidases, especially cysteine- and metallo-type peptidases. The latter revealed a more prominent effect at both the post-transcriptional and post-translational levels. Molecular Docking analysis confirmed the interaction of Cu-phendione, with high binding energy (−9.7 and −10.7 kcal·mol−1, respectively) at the active site of both TvMP50 and TvGP63 metallopeptidases. In addition, Cu-phendione significantly reduced trophozoite-mediated cytolysis in human vaginal (HMVII) and monkey kidney (VERO) epithelial cell lineages. These results highlight the antiparasitic potential of Cu-phendione by interaction with important T. vaginalis virulence factors.