In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis
Leishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 million people. The current treatment is limited and may cause severe adverse effects, and thus, the search for new drugs more effective and less toxic is relevant. We have previously investigated the immu...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-12-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2020.590544/full |
| _version_ | 1818949809217732608 |
|---|---|
| author | Dahara Keyse Carvalho Silva Dahara Keyse Carvalho Silva Jessicada Silva Teixeira Jessicada Silva Teixeira Diogo Rodrigo Magalhães Moreira Tiago Fernandes da Silva Eliezer Jesus de Lacerda Barreiro Humberto Fonseca de Freitas Samuel Silva da Rocha Pita André Lacerda Braga Teles Elisalva Teixeira Guimarães Elisalva Teixeira Guimarães Milena Botelho Pereira Soares Milena Botelho Pereira Soares |
| author_facet | Dahara Keyse Carvalho Silva Dahara Keyse Carvalho Silva Jessicada Silva Teixeira Jessicada Silva Teixeira Diogo Rodrigo Magalhães Moreira Tiago Fernandes da Silva Eliezer Jesus de Lacerda Barreiro Humberto Fonseca de Freitas Samuel Silva da Rocha Pita André Lacerda Braga Teles Elisalva Teixeira Guimarães Elisalva Teixeira Guimarães Milena Botelho Pereira Soares Milena Botelho Pereira Soares |
| author_sort | Dahara Keyse Carvalho Silva |
| collection | DOAJ |
| description | Leishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 million people. The current treatment is limited and may cause severe adverse effects, and thus, the search for new drugs more effective and less toxic is relevant. We have previously investigated the immunomodulatory effects of LASSBio-1386, an N-acylhydrazone derivative. Here we investigated the in vitro and in vivo activity of LASSBio-1386 against L. amazonensis. LASSBio-1386 inhibited the proliferation of promastigotes of L. amazonensis (EC50 = 2.4 ± 0.48 µM), while presenting low cytotoxicity to macrophages (CC50 = 74.1 ± 2.9 µM). In vitro incubation with LASSBio-1386 reduced the percentage of Leishmania-infected macrophages and the number of intracellular parasites (EC50 = 9.42 ± 0.64 µM). Also, in vivo treatment of BALB/c mice infected with L. amazonensis resulted in a decrease of lesion size, parasitic load and caused histopathological alterations, when compared to vehicle-treated control. Moreover, LASSBio-1386 caused ultrastructural changes, arrested cell cycle in G0/G1 phase and did not alter the membrane mitochondrial potential of L. amazonensis. Aiming to its possible molecular interactions, we performed docking and molecular dynamics studies on Leishmania phosphodiesterase B1 (PDB code: 2R8Q) and LASSBio-1386. The computational analyses suggest that LASSBio-1386 acts against Leishmania through the modulation of leishmanial PDE activity. In conclusion, our results indicate that LASSBio-1386 is a promising candidate for the development of new leishmaniasis treatment. |
| first_indexed | 2024-12-20T09:08:35Z |
| format | Article |
| id | doaj.art-a493384d315248e180d966857d091279 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-20T09:08:35Z |
| publishDate | 2020-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-a493384d315248e180d966857d0912792022-12-21T19:45:38ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-12-011110.3389/fphar.2020.590544590544In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensisDahara Keyse Carvalho Silva0Dahara Keyse Carvalho Silva1Jessicada Silva Teixeira2Jessicada Silva Teixeira3Diogo Rodrigo Magalhães Moreira4Tiago Fernandes da Silva5Eliezer Jesus de Lacerda Barreiro6Humberto Fonseca de Freitas7Samuel Silva da Rocha Pita8André Lacerda Braga Teles9Elisalva Teixeira Guimarães10Elisalva Teixeira Guimarães11Milena Botelho Pereira Soares12Milena Botelho Pereira Soares13Departamento de Ciências da Vida, Núcleo de Estudo e Pesquisa em Histopatologia, Universidade Estadual da Bahia (UNEB), Salvador, BrazilLaboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BrazilDepartamento de Ciências da Vida, Núcleo de Estudo e Pesquisa em Histopatologia, Universidade Estadual da Bahia (UNEB), Salvador, BrazilLaboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BrazilLaboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilLaboratório de Bioinformática e Modelagem Molecular (LaBiMM), Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, BrazilLaboratório de Bioinformática e Modelagem Molecular (LaBiMM), Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, BrazilDepartamento de Ciências da Vida, Laboratório de Modelagem Molecular Medicinal e Toxicológica, Universidade Estadual da Bahia (UNEB), Salvador, BrazilDepartamento de Ciências da Vida, Núcleo de Estudo e Pesquisa em Histopatologia, Universidade Estadual da Bahia (UNEB), Salvador, BrazilLaboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BrazilLaboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BrazilInstituto Senai de Inovação em Sistemas Avançados em Saúde, Senai/Cimatec, Salvador, BrazilLeishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 million people. The current treatment is limited and may cause severe adverse effects, and thus, the search for new drugs more effective and less toxic is relevant. We have previously investigated the immunomodulatory effects of LASSBio-1386, an N-acylhydrazone derivative. Here we investigated the in vitro and in vivo activity of LASSBio-1386 against L. amazonensis. LASSBio-1386 inhibited the proliferation of promastigotes of L. amazonensis (EC50 = 2.4 ± 0.48 µM), while presenting low cytotoxicity to macrophages (CC50 = 74.1 ± 2.9 µM). In vitro incubation with LASSBio-1386 reduced the percentage of Leishmania-infected macrophages and the number of intracellular parasites (EC50 = 9.42 ± 0.64 µM). Also, in vivo treatment of BALB/c mice infected with L. amazonensis resulted in a decrease of lesion size, parasitic load and caused histopathological alterations, when compared to vehicle-treated control. Moreover, LASSBio-1386 caused ultrastructural changes, arrested cell cycle in G0/G1 phase and did not alter the membrane mitochondrial potential of L. amazonensis. Aiming to its possible molecular interactions, we performed docking and molecular dynamics studies on Leishmania phosphodiesterase B1 (PDB code: 2R8Q) and LASSBio-1386. The computational analyses suggest that LASSBio-1386 acts against Leishmania through the modulation of leishmanial PDE activity. In conclusion, our results indicate that LASSBio-1386 is a promising candidate for the development of new leishmaniasis treatment.https://www.frontiersin.org/articles/10.3389/fphar.2020.590544/fullLeishmania amazonensisLASSBio-1386treatmentN-acyl hydrazonesphosphodiesterase |
| spellingShingle | Dahara Keyse Carvalho Silva Dahara Keyse Carvalho Silva Jessicada Silva Teixeira Jessicada Silva Teixeira Diogo Rodrigo Magalhães Moreira Tiago Fernandes da Silva Eliezer Jesus de Lacerda Barreiro Humberto Fonseca de Freitas Samuel Silva da Rocha Pita André Lacerda Braga Teles Elisalva Teixeira Guimarães Elisalva Teixeira Guimarães Milena Botelho Pereira Soares Milena Botelho Pereira Soares In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis Frontiers in Pharmacology Leishmania amazonensis LASSBio-1386 treatment N-acyl hydrazones phosphodiesterase |
| title | In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis |
| title_full | In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis |
| title_fullStr | In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis |
| title_full_unstemmed | In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis |
| title_short | In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis |
| title_sort | in vitro in vivo and in silico effectiveness of lassbio 1386 an n acyl hydrazone derivative phosphodiesterase 4 inhibitor against leishmania amazonensis |
| topic | Leishmania amazonensis LASSBio-1386 treatment N-acyl hydrazones phosphodiesterase |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2020.590544/full |
| work_keys_str_mv | AT daharakeysecarvalhosilva invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT daharakeysecarvalhosilva invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT jessicadasilvateixeira invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT jessicadasilvateixeira invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT diogorodrigomagalhaesmoreira invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT tiagofernandesdasilva invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT eliezerjesusdelacerdabarreiro invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT humbertofonsecadefreitas invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT samuelsilvadarochapita invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT andrelacerdabragateles invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT elisalvateixeiraguimaraes invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT elisalvateixeiraguimaraes invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT milenabotelhopereirasoares invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis AT milenabotelhopereirasoares invitroinvivoandinsilicoeffectivenessoflassbio1386annacylhydrazonederivativephosphodiesterase4inhibitoragainstleishmaniaamazonensis |