Unveiling the Kinomes of Leishmania infantum and L. braziliensis Empowers the Discovery of New Kinase Targets and Antileishmanial Compounds

dc.creatorBorba, Joyce Villa Verde Bastos
dc.creatorSilva, Arthur C.
dc.creatorRamos, Pablo Ivan Pereira
dc.creatorGrazzia, Nathalia
dc.creatorMiguel, Danilo Ciccone
dc.creatorMuratov, Eugene N.
dc.creatorFurnham, Nicholas
dc.creatorAndrade, Carolina Horta
dc.date2019-04-09T16:40:32Z
dc.date2019-04-09T16:40:32Z
dc.date2019
dc.date.accessioned2023-09-27T00:12:42Z
dc.date.available2023-09-27T00:12:42Z
dc.identifierBORBA, Joyce Villa Verde Bastos et al. Unveiling the kinomes of Leishmania infantum and L. braziliensis empowers the discovery of new kinase targets and antileishmanial compounds. Computational and Structural Biotechnology Journal, v. 17, p. 352–361, 2019.
dc.identifier2001-0370
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/32426
dc.identifier10.1016/j.csbj.2019.02.005
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8898565
dc.descriptionCNPq, CAPES, and FAPEG for fellowships and funding this work. E.N.M. appreciate support from NIH (grant 1U01CA207160) and CNPq (grant 400760/2014-2). NF is supported by the Medical Research Council (grantMR/K020420/1). DCM is a recipient of a young investigator award from FAPESP (2014/21129-4). CHA has a research fellow in productivity of CNPq. CHA also thanks the “L'Oréal-UNESCOABC Para Mulheres na Ciência” and “L'Oréal-UNESCO International Rising Talents” for the awards and fellowships received, which partially funded thiswork. Additionally, JVBB and ACSwere supported by fellowships from CAPES.
dc.descriptionLeishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania (NTD) endemic in 98 countries. Although some drugs are available, current treatments deal with issues such as toxicity, low efficacy, and emergence of resistance. Therefore, there is an urgent need to identify new targets for the development of new antileishmanial drugs. Protein kinases (PKs), which play an essential role in many biological processes, have become potential drug targets for many parasitic diseases. A refined bioinformatics pipeline was applied in order to define and compare the kinomes of L. infantum and L. braziliensis, species that cause cutaneous and visceral manifestations of leishmaniasis in the Americas, the latter being potentially fatal if untreated. Respectively, 224 and 221 PKs were identified in L. infantum and L. braziliensis overall. Almost all unclassified eukaryotic PKs were assigned to six of nine major kinase groups and, consequently, most have been classified into family and subfamily. Furthermore, revealing the kinomes for both Leishmania species allowed for the prioritization of potential drug targets that could be explored for discovering new drugs against leishmaniasis. Finally, we used a drug repurposing approach and prioritized seven approved drugs and investigational compounds to be experimentally tested against Leishmania. Trametinib and NMS-1286937 inhibited the growth of L. infantum and L. braziliensis promastigotes and amastigotes and therefore might be good candidates for the drug repurposing pipeline.
dc.formatapplication/pdf
dc.languageeng
dc.publisherElsevier
dc.rightsopen access
dc.subjectLeishmania infantum
dc.subjectLeishmania braziliensis
dc.subjectKinome
dc.subjectQuinases
dc.subjectReaproveitamento de drogas
dc.subjectPriorização de metas
dc.subjectLeishmania infantum
dc.subjectLeishmania braziliensis
dc.subjectKinome
dc.subjectKinases
dc.subjectDrug repurposing
dc.subjectTarget prioritization
dc.titleUnveiling the Kinomes of Leishmania infantum and L. braziliensis Empowers the Discovery of New Kinase Targets and Antileishmanial Compounds
dc.typeArticle


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