Repurposing approved protein kinase inhibitors as potent anti-leishmanials targeting Leishmania MAP kinases

Leishmaniasis is a vast array of chronic diseases caused by the protozoan parasite of the genus Leishmania transmitted by the sandfly belonging to the genus Phlebotomus (Old World) and Lutzomyia (New World). Among the various factors that contribute to the virulence and pathogenesis of the disease, protein kinases play crucial role in modulating the parasites biology in the host system. There are no specific drugs identified to treat the disease specifically. Moreover, resistance against approved anti-leishmanials has made it important to look for a few pre-clinical candidates against visceral leishmaniasis. MAP kinase is one such candidate of protein kinase family that regulates cell proliferation in eukaryotes. In this study, we have identified 23 MAPKs from Leishmania genome and have screened 12 FDA approved protein kinase inhibitors against those MAPKs in search of a potential lead for new drug exploration. Among the inhibitors, sorafenib and imatinib have been identified as potential drug candidates based on multiple criteria including binding affinity, ADME scores, absorption and their ability to cross blood-brain barrier. Furthermore, these drugs showed excellent anti-proliferative effects in Leishmania promastigotes, resulted in change of cell morphology, flagellar length, promoted cell cycle arrest through ROS generation and reduced intra-macrophage parasitic burden. Collectively, these results imply involvement of MAP kinases in infectivity and survival of the parasite and can pave the avenue for repurposing sorafenib and imatinib as anti-leishmanial agents.