Interruption of the blood-stage cycle of the malaria parasite, Plasmodium chabaudi, by protein tyrosine kinase inhibitors

Gazarini, Marcos L.; Garcia, Célia Regina da Silva

doi:10.1590/s0100-879x2003001100003

Cited by 25 publications

(13 citation statements)

References 20 publications

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“…Although no typical hydrogen bonds were identified, STU can tightly bind to CsTegu20.6, resulting in a docking energy of −7.23 kcal/mol (Figure 7B and Table S1). STU, a well-known protein kinase inhibitor, has previously been proposed as an effective drug for protozoan parasites [51,52]. Its analogues also showed strong inhibitory effects against a number of infectious agents, including antibacterial and immunosuppressive activities [53].…”

Section: Resultsmentioning

confidence: 99%

Molecular and Structural Characterization of the Tegumental 20.6-kDa Protein in Clonorchis sinensis as a Potential Druggable Target

Kim

Yoo

Lee

et al. 2017

IJMS

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The tegument, representing the membrane-bound outer surface of platyhelminth parasites, plays an important role for the regulation of the host immune response and parasite survival. A comprehensive understanding of tegumental proteins can provide drug candidates for use against helminth-associated diseases, such as clonorchiasis caused by the liver fluke Clonorchis sinensis. However, little is known regarding the physicochemical properties of C. sinensis teguments. In this study, a novel 20.6-kDa tegumental protein of the C. sinensis adult worm (CsTegu20.6) was identified and characterized by molecular and in silico methods. The complete coding sequence of 525 bp was derived from cDNA clones and encodes a protein of 175 amino acids. Homology search using BLASTX showed CsTegu20.6 identity ranging from 29% to 39% with previously-known tegumental proteins in C. sinensis. Domain analysis indicated the presence of a calcium-binding EF-hand domain containing a basic helix-loop-helix structure and a dynein light chain domain exhibiting a ferredoxin fold. We used a modified method to obtain the accurate tertiary structure of the CsTegu20.6 protein because of the unavailability of appropriate templates. The CsTegu20.6 protein sequence was split into two domains based on the disordered region, and then, the structure of each domain was modeled using I-TASSER. A final full-length structure was obtained by combining two structures and refining the whole structure. A refined CsTegu20.6 structure was used to identify a potential CsTegu20.6 inhibitor based on protein structure-compound interaction analysis. The recombinant proteins were expressed in Escherichia coli and purified by nickel-nitrilotriacetic acid affinity chromatography. In C. sinensis, CsTegu20.6 mRNAs were abundant in adult and metacercariae, but not in the egg. Immunohistochemistry revealed that CsTegu20.6 localized to the surface of the tegument in the adult fluke. Collectively, our results contribute to a better understanding of the structural and functional characteristics of CsTegu20.6 and homologs of flukes. One compound is proposed as a putative inhibitor of CsTegu20.6 to facilitate further studies for anthelmintics.

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Section: Resultsmentioning

confidence: 99%

Molecular and Structural Characterization of the Tegumental 20.6-kDa Protein in Clonorchis sinensis as a Potential Druggable Target

Kim

Yoo

Lee

et al. 2017

IJMS

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“…Additional S. neurona CMGC kinases identified include SRPK (SRCN_1236), CLK (SRCN_1479), PRP4 (SRCN_2845), DYRK (SRCN_1611), GSK-1A (SRCN_1731), GSK-1B (SRCN_1732), CK2 (SRCN_6427), ERK7 (SRCN_6472), MAPK-2 (SRCN_5365) and MAPK-1 (SRCN_4209), all of which fall in orthologous clades with robust bootstrap values. SRPK, CLK and PRP4 kinases most likely have crucial roles in parasite survival given their involvement in cycle-regulatory regulation [56,57,58], potentially via alternative mRNA splicing. Inhibition of PfCLK-mediated SR protein phosphorylation impaired blood stage replication and malaria transmission in Plasmodium [59].…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases

Murungi

Kariithi

2017

Pathogens

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The apicomplexan parasite Sarcocystis neurona causes equine protozoal myeloencephalitis (EPM), a degenerative neurological disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs) have been implicated in a myriad of critical functions, such as host cell invasion, cell cycle progression and host immune response evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. We identified 97 putative PKs clustering within the various eukaryotic kinase groups. Although containing the universally-conserved PKA (AGC group), S. neurona kinome was devoid of PKB and PKC. Moreover, the kinome contains the six-conserved apicomplexan CDPKs (CAMK group). Several OPK atypical kinases, including ROPKs 19A, 27, 30, 33, 35 and 37 were identified. Notably, S. neurona is devoid of the virulence-associated ROPKs 5, 6, 18 and 38, as well as the Alpha and RIO kinases. Two out of the three S. neurona CK1 enzymes had high sequence similarities to Toxoplasma gondii TgCK1-α and TgCK1-β and the Plasmodium PfCK1. Further experimental studies on the S. neurona putative PKs identified in this study are required to validate the functional roles of the PKs and to understand their involvement in mechanisms that regulate various cellular processes and host-parasite interactions. Given the essentiality of apicomplexan PKs in the survival of apicomplexans, the current study offers a platform for future development of novel therapeutics for EPM, for instance via application of PK inhibitors to block parasite invasion and development in their host.

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“…Pharmacological experiments on cultured P. falciparum blood stages suggested that cAMP-PKA dependent pathways can regulate cytosolic calcium levels and thereby delay parasitic maturation in-vitro [17]. Gazarini et al [18] showed protein kinase inhibitors interrupts the blood stage cycle of the rodent malaria parasite, Plasmodium chabaudi. None of those kinase inhibitors are as yet widely used in humans.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitors: New class of antimalarials on the horizon?

Pathak

Colah

Ghosh

2015

Blood Cells, Molecules, and Diseases

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Interruption of the blood-stage cycle of the malaria parasite, Plasmodium chabaudi, by protein tyrosine kinase inhibitors

Cited by 25 publications

References 20 publications

Molecular and Structural Characterization of the Tegumental 20.6-kDa Protein in Clonorchis sinensis as a Potential Druggable Target

Molecular and Structural Characterization of the Tegumental 20.6-kDa Protein in Clonorchis sinensis as a Potential Druggable Target

Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases

Tyrosine kinase inhibitors: New class of antimalarials on the horizon?

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