A multi-species phenotypic screening assay for leishmaniasis drug discovery shows that active compounds display a high degree of species-specificity

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dc.contributorCentro de Biotecnologiapt_BR
dc.contributor.authorAlcantara, Laura M.pt_BR
dc.contributor.authorFerreira, Thalita Camêlo da Silvapt_BR
dc.contributor.authorFontana, Vanessapt_BR
dc.contributor.authorChatelain, Ericpt_BR
dc.contributor.authorMoraes, Carolina Borsoipt_BR
dc.contributor.authorFreitas-Junior, Lucio Holanda Gondimpt_BR
dc.date.accessioned2020-07-09T21:28:00Z-
dc.date.available2020-07-09T21:28:00Z-
dc.date.issued2020pt_BR
dc.identifier.citationAlcantara LM., Ferreira TCS, Fontana V, Chatelain E, Moraes CB, Freitas-Junior LHG. A multi-species phenotypic screening assay for leishmaniasis drug discovery shows that active compounds display a high degree of species-specificity. Molecules. 2020 May;25(11):2551. doi:10.3390/molecules25112551.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/3058-
dc.description.abstractHigh genetic and phenotypic variability between Leishmania species and strains within species make the development of broad-spectrum antileishmanial drugs challenging. Thus, screening panels consisting of several diverse Leishmania species can be useful in enabling compound prioritization based on their spectrum of activity. In this study, a robust and reproducible high content assay was developed, and 1280 small molecules were simultaneously screened against clinically relevant cutaneous and visceral species: L. amazonensis, L. braziliensis, and L. donovani. The assay is based on THP-1 macrophages infected with stationary phase promastigotes and posterior evaluation of both compound antileishmanial activity and host cell toxicity. The profile of compound activity was species-specific, and out of 51 active compounds, only 14 presented broad-spectrum activity against the three species, with activities ranging from 52% to 100%. Notably, the compounds CB1954, Clomipramine, Maprotiline, Protriptyline, and ML-9 presented pan-leishmanial activity, with efficacy greater than 70%. The results highlight the reduced number of compound classes with pan-leishmanial activity that might be available from diversity libraries, emphasizing the need to screen active compounds against a panel of species and strains. The assay reported here can be adapted to virtually any Leishmania species without the need for genetic modification of parasites, providing the basis for the discovery of broad spectrum anti-leishmanial agents.pt_BR
dc.description.sponsorship(DNDi) Drugs for Neglected Diseases Initiativept_BR
dc.description.sponsorshipSwiss Agency for Development and Cooperation (SDC)pt_BR
dc.description.sponsorshipUK Aidpt_BR
dc.description.sponsorship(MSF) Médecins sans frontièrespt_BR
dc.description.sponsorship(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológicopt_BR
dc.description.sponsorship(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.format.extent2551pt_BR
dc.language.isoEnglishpt_BR
dc.relation.ispartofMoleculespt_BR
dc.rightsOpen accesspt_BR
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/pt_BR
dc.titleA multi-species phenotypic screening assay for leishmaniasis drug discovery shows that active compounds display a high degree of species-specificitypt_BR
dc.typeArticlept_BR
dc.rights.licenseCC BYpt_BR
dc.identifier.doi10.3390/molecules25112551pt_BR
dc.identifier.urlhttps://doi.org/10.3390/molecules25112551pt_BR
dc.contributor.externalLaboratório Nacional de Biociências (LNBio)¦¦Brasilpt_BR
dc.contributor.external(USP) Universidade de São Paulopt_BR
dc.contributor.externalDrugs for Neglected Diseases Initiative (DNDi)¦¦Suíçapt_BR
dc.contributor.externalUniversity of Liverpool¦¦Inglaterrapt_BR
dc.contributor.external(UNIFESP) Universidade Federal de São Paulo¦¦Brasilpt_BR
dc.identifier.citationvolume25pt_BR
dc.identifier.citationissue11pt_BR
dc.subject.keywordLeishmaniapt_BR
dc.subject.keywordleishmaniasis drug discoverypt_BR
dc.subject.keywordphenotypic screeningpt_BR
dc.subject.keywordLeishmania speciespt_BR
dc.relation.ispartofabbreviatedMoleculespt_BR
dc.identifier.citationabntv. 25, n. 11, 2551, mai. 2020pt_BR
dc.identifier.citationvancouver2020 May;25(11):2551pt_BR
dc.contributor.butantanFerreira, Thalita Camêlo da Silva|:Aluno|:Centro de Biotecnologia|:pt_BR
dc.contributor.butantanFreitas-Junior, Lucio Holanda Gondim|:Colaborador|:|:Autor de correspondênciapt_BR
dc.sponsorship.butantan(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológico¦¦140907/2013-0pt_BR
dc.sponsorship.butantan(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológico¦¦140831/2015-0pt_BR
dc.sponsorship.butantanDrugs for Neglected Diseases Initiative (DNDi)¦¦pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦15/10436-6pt_BR
dc.sponsorship.butantanMédecins sans frontières (MSF)¦¦pt_BR
dc.sponsorship.butantanSwiss Agency for Development and Cooperation (SDC)¦¦pt_BR
dc.sponsorship.butantanUK Aid¦¦pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
dc.description.dbindexedYespt_BR
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