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

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.

Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

“…protein kinases ( 19 ), and Leishmania sp. kinases ( 20 ). In the present work, we used a comparative phylogenomics approach in order to identify predicted targets of P. falciparum and P. vivax , which are present in the parasite’s proteome but expected to be absent in humans.…”

Leishmania Protein Kinases: Important Regulators of the Parasite Life Cycle and Molecular Targets for Treating Leishmaniasis

“…The leishmanial kinome consists of 175–195 eukaryotic protein kinases (ePKs) depending on the Leishmania species and represents roughly 2% of the encoded proteins [ 35 , 36 , 37 ]. Catalytic domain similarity according to Manning et al, has classified Leishmania ePKs in several groups, namely CMGC, AGC, CAMK, CK1, STE and “other” (several kinase families that do not fit within any of the other main kinase groups) [ 38 ].…”

“…Catalytic domain similarity according to Manning et al, has classified Leishmania ePKs in several groups, namely CMGC, AGC, CAMK, CK1, STE and “other” (several kinase families that do not fit within any of the other main kinase groups) [ 38 ]. Notably, the Leishmania genome does not encode for ePKs that belong to tyrosine kinases, tyrosine kinase-like (TKL) and receptor guanylate cyclase (RGC) groups while dual specificity kinases are present [ 35 , 36 ].…”

Evaluation of different concentrations of imatinib on the viability of Leishmania major: An In Vitro study

“…[7] They are further classified into nine groups, based on their sequence similarity, according to the manning classification: (1) Protein kinase of A, G, and C; (the AGC group) (2)– Ca+/CAM-dependent kinases (CAMK group); (3)– cyclin-dependent kinases (CDK) (CMGC group), mitogen-activated protein kinases (MAPK), GSK3, and CLK; (4) CK1 – casein kinase 1 (CK) 1; (5)– homologs of yeast sterile 7, 11, and 20; (STE group) (6)– receptor guanylate cyclases (RGC group) (7) Tyrosine kinase (TK) (group – TK); (8) – TK-like (TKL group); and (9) “Other” group – several. [8]…”

“…[16] Since the serious limitations such as toxicity to other cells and lack of efficacy in endemic areas show the need for new antileishmanial compounds, and thus the development of safe, potent, and cost-effective antileishmanial agents are a critical public health priority. [8]…”