New multienzymatic complex formed between human cathepsin D and snake venom phospholipase A2

Background Cathepsin D (CatD) is a lysosomal proteolytic enzyme expressed in almost all tissues and organs. This protease is a multifunctional enzyme responsible for essential biological processes such as cell cycle regulation, differentiation, migration, tissue remodeling, neuronal growth, ovulation, and apoptosis. The overexpression and hypersecretion of CatD have been correlated with cancer aggressiveness and tumor progression, stimulating cancer cell proliferation, fibroblast growth, and angiogenesis. In addition, some studies report its participation in neurodegenerative diseases and inflammatory processes. In this regard, the search for new inhibitors from natural products could be an alternative against the harmful effects of this enzyme. Methods An investigation was carried out to analyze CatD interaction with snake venom toxins in an attempt to find inhibitory molecules. Interestingly, human CatD shows the ability to bind strongly to snake venom phospholipases A2 (svPLA2), forming a stable muti-enzymatic complex that maintains the catalytic activity of both CatD and PLA2. In addition, this complex remains active even under exposure to the specific inhibitor pepstatin A. Furthermore, the complex formation between CatD and svPLA2 was evidenced by surface plasmon resonance (SPR), two-dimensional electrophoresis, enzymatic assays, and extensive molecular docking and dynamics techniques. Conclusion The present study suggests the versatility of human CatD and svPLA2, showing that these enzymes can form a fully functional new enzymatic complex.

In vitro and ex vivo antiplasmodial activity of 1-(3-benzyloxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propan-1-one) against circulating strains of Plasmodium spp. in the state of Rondônia, Brazil

Abstract Malaria is a disease caused by Plasmodium spp. protozoa. The ability of Plasmodium to develop resistance to current antimalarial drugs makes the study of chemotherapeutic alternatives extremely important. This study aimed to evaluate the antimalarial activity of compound 3286938 (1-(3-benzyloxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propan-1-one), which presents in its structure a 3,4,5-trimethoxyphenyl group, in vitro, using the W2 strain of P. falciparum and against circulating strains of P. vivax and P. falciparum from the state of Rondônia. The compound 3286938 obtained an IC50 of 24.4 µM against the W2 strain of P. falciparum, and against the circulating strains, it presented a median (MD)=38.7 µM for P. vivax and MD=6.7 µM for P. falciparum. As for toxicity, 3286938 showed CC50 > 500 µM for VERO and HepG2 strains with a selectivity index greater than 12.9, a ratio calculated for P. falciparum and P. vivax regarding Vero and HepG2 cells. The compound was not considered hemolytic in in vitro assays, thus indicating the specificity of its antiplasmodial action. Based on the results presented, and considering the unprecedented character of the compound, it can be concluded that 3286938 was shown to be promising for complementary in vitro and in vivo studies aiming to produce effective antiplasmodial action.

Antiprotozoal action of synthetic cinnamic acid analogs

Abstract INTRODUCTION Leishmaniasis, Chagas disease, and malaria cause morbidity globally. The drugs currently used for treatment have limitations. Activity of cinnamic acid analogs against Leishmania spp., Trypanosoma cruzi, and Plasmodium falciparum was evaluated in the interest of identifying new antiprotozoal compounds. METHODS In vitro effects of analogs against L. braziliensis, L. infantum chagasi, T. cruzi, and P. falciparum, and hemolytic and cytotoxic activities on NCTC 929 were determined. RESULTS Three analogs showed leishmanicidal and tripanocidal activity. No antiplasmodial, hemolytic, or cytotoxic activity was observed. CONCLUSIONS Antiprotozoal activity of analogs against L. infantum braziliensis, L. infantum chagasi, and T. cruzi was demonstrated.