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.
Highlights
Leishmaniasis is a parasitic disease caused by the etiologic agent Leishmania spp
We developed and applied a robust bioinformatics pipeline that enabled us to classify most of the protein kinases at a subfamily level
A complementary target prioritization approach was performed by constructing a protein network interaction of kinase proteins through STRING [29] v. 10.0 web server and the resulting network was analyzed from a graph-theoretic perspective
Summary
Leishmaniasis is a parasitic disease caused by the etiologic agent Leishmania spp. The disease is clinically classified based on its manifestations as Visceral Leishmaniasis (VL) and Cutaneous Leishmaniasis (CL) and on the Leishmania species parasitizing the host. Two important human pathogen species are Leishmania infantum, which cause New World and Old World VL, and Leishmania braziliensis, which is among the species causing CL in the Americas [2,3,4]. The current treatment of VL and CL rely on pentavalent antimonials - amphotericin B, paromicine, pentamidine, and miltefosine - which have issues with toxicity and administration. Their effectiveness is compromised due to the emergence of resistant strains. There is a need for developing new drugs against leishmaniasis [7,8]
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