Article
Unveiling the Kinomes of Leishmania infantum and L. braziliensis Empowers the Discovery of New Kinase Targets and Antileishmanial Compounds
Registro en:
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.
2001-0370
10.1016/j.csbj.2019.02.005
Autor
Borba, Joyce Villa Verde Bastos
Silva, Arthur C.
Ramos, Pablo Ivan Pereira
Grazzia, Nathalia
Miguel, Danilo Ciccone
Muratov, Eugene N.
Furnham, Nicholas
Andrade, Carolina Horta
Resumen
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. 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.
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