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

Autor(es)

Borba, Joyce V. B. ^[1] ; Silva, Arthur C. ^[1] ; Ramos, Pablo I. P. ^[2] ; Grazzia, Nathalia ^[3] ; Miguel, Danilo C. ^[3] ; Muratov, Eugene N. ^{[4, 5]} ; Furnham, Nicholas ^[6] ; Andrade, Carolina H. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Goias, Fac Farm, Labmol Lab Mol Modeling & Drug Design, BR-74605510 Goiania, Go - Brazil

^[2] Fundacao Oswaldo Cruz FIOCRUZ, Inst Goncalo Moniz, BR-40296710 Salvador, BA - Brazil

^[3] State Univ Campinas UNICAMP, Biol Inst, Dept Anim Biol, LEBIL Lab Leishmania Biol Infect Studies, Campinas, SP - Brazil

^[4] Odessa Natl Polytech Univ, Dept Chem Technol, UA-65000 Odessa - Ukraine

^[5] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Lab Mol Modeling, Chapel Hill, NC 27599 - USA

^[6] London Sch Hyg & Trop Med, Dept Pathogen Mol Biol, London - England

• Tipo de documento: Artigo Científico
• Fonte: COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL; v. 17, p. 352-361, 2019.
• Citações Web of Science: 0

Resumo

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 bioin formatics 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 eukalyotic 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. (C) 2019 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. (AU)

• Processo FAPESP: 14/21129-4 - O papel das proteínas ligantes de ácidos graxos na infecção de macrófagos por Leishmania: um alvo potencial para novas drogas contra leishmaniose
• Beneficiário: Danilo Ciccone Miguel
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores