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Lethal action of Licarin A derivatives in Leishmania (L.) infantum Imbalance of calcium and bioenergetic metabolism

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Autor(es):
Levatti, Erica V. de Castro ; Costa-Silva, Thais A. ; Morais, Thiago R. ; Fernandes, Joao Paulo S. ; Lago, Joao Henrique G. ; Tempone, Andre G.
Número total de Autores: 6
Tipo de documento: Artigo Científico
Fonte: Biochimie; v. 208, p. 10-pg., 2023-05-22.
Resumo

Natural metabolites present an extraordinary chemo-diversity and have been used as the inspiration for new drugs. Considering the need for new treatments against the neglected parasitic disease leishmaniasis, three semi-synthetic derivatives of natural neolignane licarin A were prepared: O-acetyl (1a), Oallyl (1b), and 5-allyl (1c). Using an ex vivo assay, compounds 1a, 1b, and 1c showed activity against the intracellular amastigotes of Leishmania (L.) infantum, with IC50 values of 9, 13, and 10 mM, respectively. Despite no induction of hemolytic activity, only compound 1b resulted in mammalian cytotoxicity (CC50 1/4 64 mM). The most potent compounds (1a and 1c) resulted in selectivity indexes >18. The mechanism of action of compound 1c was evaluated by fluorescent/luminescent based techniques and MALDI-TOF/MS. After a short incubation period, increased levels of the cytosolic calcium were observed in the parasites, with alkalinization of the acidocalcisomes. Compound 1c also induced mitochondrial hyperpolarization, resulting in decreased levels of ATP without altering the reactive oxygen species (ROS). Neither plasma membrane damages nor DNA fragmentation were observed after the treatment, but a reduction in the cellular proliferation was detected. Using MALDI-TOF/MS, mass spectral alterations of promastigote proteins were observed when compared to untreated and miltefosine-treated groups. This chemically modified neolignan induced lethal alterations of the bioenergetic and protein metabolism of Leishmania. Future PKPD and animal efficacy studies are needed to optimize this promising natural-derived compound. (c) 2023 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU)

Processo FAPESP: 21/02789-7 - Busca de metabólitos bioativos com ação antiparasitária em espécies vegetais de regiões de Mata Atlântica e Cerrado - uma abordagem química, fenotípica e metabolômica
Beneficiário:João Henrique Ghilardi Lago
Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular
Processo FAPESP: 21/04464-8 - Protótipos microbianos e vegetais como candidatos a fármacos para protozooses negligenciadas e bactérias multirresistentes
Beneficiário:André Gustavo Tempone Cardoso
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 17/50333-7 - Plano de desenvolvimento institucional em pesquisa do Instituto Adolfo Lutz (PDIp)
Beneficiário:Carlos Henrique Camargo
Modalidade de apoio: Auxílio à Pesquisa - Programa Modernização de Institutos Estaduais de Pesquisa