Identification of novel Zika virus NS3 protease inhibitors with different inhibition modes by integrative experimental and computational approaches.

Zika virus (ZIKV) infection is associated with severe neurological disorders and congenital malformation. Despite efforts to eradicate the disease, there is still neither vaccine nor approved drugs to treat ZIKV infection. The NS2B-NS3 protease is a validated drug target since it is essential to polyprotein virus maturation. In the present study, we describe an experimental screening of 2,320 compounds from the chemical library of the Muséum National d'Histoire Naturelle of Paris on ZIKV NS2B-NS3 protease. A total of 96 hits were identified with 90% or more of inhibitory activity at 10 µM. Amongst the most active compounds, five were analyzed for their inhibitory mechanisms by kinetics assays and computational approaches such as molecular docking. 2-(3-methoxyphenoxy) benzoic acid (compound 945) show characteristics of a competitive inhibition (Ki = 0.49 µM) that was corroborated by its molecular docking at the active site of the NS2B-NS3 protease. Taxifolin (compound 2292) behaves as an allosteric inhibitor whereas 3,8,9-trihydroxy-2-methyl-1H-phenalen-1-one (compound 128), harmol (compound 368) and anthrapurpurin (compound 1499) show uncompetitive inhibitions. These new NS2B-NS3 protease inhibitors are valuable hits to further hit-to-lead optimization.

Oligopeptidase B, a missing enzyme in mammals and a potential drug target for trypanosomatid diseases.

Oligopeptidases B (OPB) belong to the S9 prolyl oligopeptidase family and are expressed in prokaryotes, some eukaryotes and in some higher plants. OPB is not found in any of the mammalian genomes available to date. Evidences indicate that OPB participates in the infections caused by trypanosomatids Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp and therefore it is considered an important virulence factor. Trypanosomatids from the genera Leishmania and Trypanosoma also present other OPB, named OPB2. A more accurate investigation of trypanosomatid OPB sequences brought attention to what could be a third OPB sequence (OPB3). This review aims to discuss biochemical, structural, phylogenetic and functional properties of OPB and its potential as target for the development of drugs against Chagas disease, leishmaniasis and African trypanosomiasis.

Essential oils: in vitro activity against Leishmania amazonensis, cytotoxicity and chemical composition.

BACKGROUND: The current chemotherapy for cutaneous leishmaniosis (CL) has a series of drug limitations such as toxic side effects, long duration, high costs and drug resistance, which requires the development of new drugs or effective alternatives to the CL treatment. Essential oils (EOs) are complex mixtures of secondary metabolites from various plants. It has been shown that several EOs, or their constituents, have inhibitory activity against protozoa. Thus, this study aims to evaluate the biological activity of different essential oils (EOs) on Leishmania (L.) amazonensis promastigotes forms, as well as their cytotoxicity on mammalian cells and chemical composition. METHODS: Sixteen EOs were evaluated by mean of IC50/24 h and cytotoxicity against L6 cells (CC50/24 h) using Resazurin assay. Only those EOs that presented better results for IC50/24 h were submitted to GC-MS analysis to determine their chemical constitution. RESULTS: The EO from Cinnamodendron dinisii, Matricaria chamomilla, Myroxylon peruiferum, Salvia sclarea, Bulnesia sarmientoi, Ferula galbaniflua, Siparuna guianensis and Melissa officinalis were the most active against L. amazonensis with IC50/24 h ranging from 54.05 to 162.25 µg/mL. Analysis of EOs by GC-MS showed mainly the presence of ß-farnesene (52.73 %) and bisabolol oxide (12.09 %) for M. chamomilla; α-copaene (13.41 %), safrole (8.35 %) and δ-cadinene (7.08 %) for M. peruiferum; linalool (28.80 %) and linalyl acetate (60.08 %) for S. sclarea; guaiol (48.29 %) and 2-undecanone (19.49 %) for B. sarmientoi; ethyl phthalate (13.09 %) and methyl-8-pimaren-18-oate (41.82 %) for F. galbaniflua; and neral (37.18 %) and citral (5.02 %) for M. officinalis. CONCLUSION: The EO from F. galbaniflua showed to be effective against L. amazonensis promastigotes forms and presented low cytotoxic activity against L6 cells. Thus, it represents a strong candidate for future studies aiming its molecular activity on these pathogenic parasites.