| Author | Borba, Joyce Villa Verde Bastos | |
| Author | Silva, Arthur C. | |
| Author | Ramos, Pablo Ivan Pereira | |
| Author | Grazzia, Nathalia | |
| Author | Miguel, Danilo Ciccone | |
| Author | Muratov, Eugene N. | |
| Author | Furnham, Nicholas | |
| Author | Andrade, Carolina Horta | |
| Access date | 2019-04-09T16:40:32Z | |
| Available date | 2019-04-09T16:40:32Z | |
| Document date | 2019 | |
| Citation | BORBA, 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. | pt_BR |
| ISSN | 2001-0370 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/32426 | |
| Sponsorship | CNPq, 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. | pt_BR |
| Language | eng | pt_BR |
| Publisher | Elsevier | pt_BR |
| Rights | open access | pt_BR |
| Subject in Portuguese | Leishmania infantum | pt_BR |
| Subject in Portuguese | Leishmania braziliensis | pt_BR |
| Subject in Portuguese | Kinome | pt_BR |
| Subject in Portuguese | Quinases | pt_BR |
| Subject in Portuguese | Reaproveitamento de drogas | pt_BR |
| Subject in Portuguese | Priorização de metas | pt_BR |
| Title | Unveiling the Kinomes of Leishmania infantum and L. braziliensis Empowers the Discovery of New Kinase Targets and Antileishmanial Compounds | pt_BR |
| Type | Article | pt_BR |
| DOI | 10.1016/j.csbj.2019.02.005 | |
| Abstract | Leishmaniasis 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. | pt_BR |
| Affilliation | Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, GO, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, GO, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
| Affilliation | State University of Campinas. Biology Institute. Laboratory of Leishmania Biology Infection Studies. Department of Animal Biology. Campinas, SP, Brasil. | pt_BR |
| Affilliation | State University of Campinas. Biology Institute. Laboratory of Leishmania Biology Infection Studies. Department of Animal Biology. Campinas, SP, Brasil. | pt_BR |
| Affilliation | University of North Carolina. Eshelman School of Pharmacy. Laboratory for Molecular Modeling. Division of Chemical Biology and Medicinal Chemistry. Chapel Hill, NC, USA / Odessa National Polytechnic University. Department of Chemical Technology. Odessa, Ukraine. | pt_BR |
| Affilliation | London School of Hygiene and Tropical Medicine. Department of Pathogen Molecular Biology. London, UK. | pt_BR |
| Affilliation | Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, GO, Brasil. | pt_BR |
| Subject | Leishmania infantum | pt_BR |
| Subject | Leishmania braziliensis | pt_BR |
| Subject | Kinome | pt_BR |
| Subject | Kinases | pt_BR |
| Subject | Drug repurposing | pt_BR |
| Subject | Target prioritization | pt_BR |
