Heme oxygenase-1 in protozoan infections: A tale of resistance and disease tolerance.

Heme oxygenase (HO-1) mediates the enzymatic cleavage of heme, a molecule with proinflammatory and prooxidant properties. HO-1 activity deeply impacts host capacity to tolerate infection through reduction of tissue damage or affecting resistance, the ability of the host to control pathogen loads. In this Review, we will discuss the contribution of HO-1 in different and complex protozoan infections, such as malaria, leishmaniasis, Chagas disease, and toxoplasmosis. The complexity of these infections and the pleiotropic effects of HO-1 constitute an interesting area of study and an opportunity for drug development.

Targeting CYP51 for drug design by the contributions of molecular modeling.

CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles.

Targeting caspases in intracellular protozoan infections.

Caspases are cysteine aspartases acting either as initiators (caspases 8, 9, and 10) or executioners (caspases 3, 6, and 7) to induce programmed cell death by apoptosis. Parasite infections by certain intracellular protozoans increase host cell life span by targeting caspase activation. Conversely, caspase activation, followed by apoptosis of lymphocytes and other cells, prevents effective immune responses to chronic parasite infection. Here we discuss how pharmacological inhibition of caspases might affect the immunity to protozoan infections, by either blocking or delaying apoptosis.

Purine nucleoside phosphorylase: a potential target for the development of drugs to treat T-cell- and apicomplexan parasite-mediated diseases.

Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of nucleosides and deoxynucleosides, generating ribose 1-phosphate and the purine base, which is an important step of purine catabolism pathway. The lack of such an activity in humans, owing to a genetic disorder, causes T-cell impairment, and thus drugs that inhibit human PNP activity have the potential of being utilized as modulators of the immunological system to treat leukemia, autoimmune diseases, and rejection in organ transplantation. Besides, the purine salvage pathway is the only possible way for apicomplexan parasites to obtain the building blocks for RNA and DNA synthesis, which makes PNP from these parasites an attractive target for drug development against diseases such as malaria. Hence, a number of research groups have made efforts to elucidate the mechanism of action of PNP based on structural and kinetic studies. It is conceivable that the mechanism may be different for PNPs from diverse sources, and influenced by the oligomeric state of the enzyme in solution. Furthermore, distinct transition state structures can make possible the rational design of specific inhibitors for human and apicomplexan enzymes. Here, we review the current status of these research efforts to elucidate the mechanism of PNP-catalyzed chemical reaction, focusing on the mammalian and Plamodium falciparum enzymes, targets for drug development against, respectively, T-Cell- and Apicomplexan parasites-mediated diseases.

Fosforilación en células eucarióticas: papel de fosfatasas y quinasas en la biología, patogenia y control de protozoosis tisulares y sanguíneas / Phosphorylation in eukaryotic cells: role of phosphatases and kinases in biology, pathogenesis and control of intracellular and bloodstream protozoa

Cells respond to environmental or cellular changes, rapidly switching protein activities from one state to another. In eukaryotes, a way to achieve these changes is through protein phosphorylation cycles, involving independent protein kinase and protein phosphatase activities. Current evidences show that phosphatases and kinases are also involved in the molecular basis of immune response and in diseases such as diabetes obesity and Alzheimer. In protozoan parasites like Trypanosoma and Leishmania, several kinases and phosphatases have been identified, many of them have been cloned but in several cases their biological role remains undetermined. In this review, the state-of-the art is summarized and the role of phosphatases and kinases in biological phenomena such as remodeling, invasion and pathogenic capacity of protozoan parasites is described. The real chance to use these components of signal transduction pathways as target for chemotherapeutic intervention is also discussed

[Phosphorylation in eukaryotic cells. Role of phosphatases and kinases in the biology, pathogenesis and control of intracellular and bloodstream protozoa]. / Fosforilación en células eucarióticas. Papel de fosfatasas y quinasas en la biología, patogenia y control de protozoosis tisulares y sanguíneas.

Cells respond to environmental or cellular changes, rapidly switching protein activities from one state to another. In eukaryotes, a way to achieve these changes is through protein phosphorylation cycles, involving independent protein kinase and protein phosphatase activities. Current evidences show that phosphatases and kinases are also involved in the molecular basis of immune response and in disease such as diabetes obesity and Alzheimer. In protozoan parasites like Trypanosoma and Leishmania, several kinases and phosphatases have been identified, many of them have been cloned but in several cases their biological role remains undetermined. In this review, the state-of-the art is summarized and the role of phosphatases and kinases in biological phenomena such as remodeling, invasion and pathogenic capacity of protozoan parasites is described. The real chance to use these components of signal transduction pathways as target for chemotherapeutic intervention is also discussed (Rev Méd Chile 2000; 128: 1150-60).