期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2019
卷号：17
页码：352-361
DOI：10.1016/j.csbj.2019.02.005
出版社：Computational and Structural Biotechnology Journal
摘要：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. infantumand 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. infantumand L. braziliensisoverall. 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 Leishmaniaspecies 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. infantumand L. braziliensispromastigotes and amastigotes and therefore might be good candidates for the drug repurposing pipeline.
