| Autor: |
Paes SS; Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil., Silva-Silva JV; Laboratory of Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21041-250, RJ, Brazil.; Laboratory of Medicinal and Computational Chemistry, Institute of Physics of São Carlos, University of São Paulo, São Carlos 13418-900, SP, Brazil., Portal Gomes PW; Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92123, USA., Silva LOD; Department of Natural Sciences, Pará State University, Belém 66095-015, PA, Brazil., Costa APLD; Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil., Lopes Júnior ML; Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil., Hardoim DJ; Laboratory of Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21041-250, RJ, Brazil., Moragas-Tellis CJ; Laboratory of Natural Products for Public Health, Pharmaceutical Technology Institute, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil., Taniwaki NN; Electron Microscopy Nucleus, Adolfo Lutz Institute, São Paulo 01246-000, SP, Brazil., Bertho AL; Laboratory of Immunoparasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil.; Flow Cytometry Core Facility, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil., Molfetta FA; Laboratory of Molecular Modeling, Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil., Almeida-Souza F; Laboratory of Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21041-250, RJ, Brazil.; Postgraduate Program in Animal Science, State University of Maranhão, Sao Luis 65055-310, MA, Brazil., Santos LS; Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil., Calabrese KDS; Laboratory of Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21041-250, RJ, Brazil. |
| Abstrakt: |
Leishmaniasis is a complex disease caused by infection with different Leishmania parasites. The number of medications used for its treatment is still limited and the discovery of new drugs is a valuable approach. In this context, here we describe the in vitro leishmanicidal activity and the in silico interaction between trypanothione reductase (TryR) and (-)-5-demethoxygrandisin B from the leaves of Virola surinamensis (Rol.) Warb. The compound (-)-5-demethoxygrandisin B was isolated from V. surinamensis leaves, a plant found in the Brazilian Amazon, and it was characterized as (7R,8S,7'R,8'S)-3,4,5,3',4'-pentamethoxy-7,7'-epoxylignan. In vitro antileishmanial activity was examined against Leishmania amazonensis , covering both promastigote and intracellular amastigote phases. Cytotoxicity and nitrite production were gauged using BALB/c peritoneal macrophages. Moreover, transmission electron microscopy was applied to probe ultrastructural alterations, and flow cytometry assessed the shifts in the mitochondrial membrane potential. In silico methods such as molecular docking and molecular dynamics assessed the interaction between the most stable configuration of (-)-5-demethoxygrandisin B and TryR from L. infantum (PDB ID 2JK6). As a result, the (-)-5-demethoxygrandisin B was active against promastigote (IC 50 7.0 µM) and intracellular amastigote (IC 50 26.04 µM) forms of L. amazonensis , with acceptable selectivity indexes. (-)-5-demethoxygrandisin B caused ultrastructural changes in promastigotes, including mitochondrial swelling, altered kDNA patterns, vacuoles, vesicular structures, autophagosomes, and enlarged flagellar pockets. It reduced the mitochondria membrane potential and formed bonds with important residues in the TryR enzyme. The molecular dynamics simulations showed stability and favorable interaction with TryR. The compound targets L. amazonensis mitochondria via TryR enzyme inhibition. |
