Targeting Protein Kinases in the Malaria Parasite: Update of an Antimalarial Drug Target

2012 ◽  
Vol 12 (5) ◽  
pp. 456-472 ◽  
Author(s):  
Veronica M. Zhang ◽  
Marina Chavchich ◽  
Norman C. Waters
Keyword(s):  
Protein Kinases ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Malaria Parasite

scholarly journals Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Tabish Qidwai ◽  
Farrukh Jamal ◽  
Mohd Y. Khan ◽  
Bechan Sharma
Keyword(s):  
Antimalarial Drug ◽  
Metabolic Pathways ◽  
Drug Target ◽  
Drug Targets ◽  
Malaria Parasite ◽  
Biosynthetic Pathway ◽  
Comprehensive Analysis ◽  
Isoprenoid Biosynthesis ◽  
Biosynthesis Pathway ◽  
Novel Targets

Emergence of rapid drug resistance to existing antimalarial drugs inPlasmodium falciparumhas created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

scholarly journals ATP2, the essential P4-ATPase of malaria parasites, catalyzes lipid-dependent ATP hydrolysis in complex with a Cdc50 β-subunit

2020 ◽  
Author(s):  
Anaïs Lamy ◽  
Ewerton Macarini-Bruzaferro ◽  
Alex Perálvarez-Marín ◽  
Marc le Maire ◽  
José Luis Vázquez-Ibar
Keyword(s):  
Antimalarial Drug ◽  
Drug Target ◽  
Malaria Parasite ◽  
Atp Hydrolysis ◽  
Head Groups ◽  
Phospholipid Distribution ◽  
Phosphatidylinositol 4 ◽  
P Type ◽  
Efficient Mechanisms

ABSTRACTEfficient mechanisms of lipid transport are indispensable for the Plasmodium malaria parasite along the different stages of its intracellular life-cycle. Gene targeting approaches have recently revealed the irreplaceable role of the Plasmodium-encoded type 4 P-type ATPases (P4-ATPases or lipid flippases), ATP2, together with its potential involvement as antimalarial drug target. In eukaryotic membranes, P4-ATPases assure their asymmetric phospholipid distribution by translocating phospholipids from the outer to the inner leaflet. As ATP2 is a yet putative transporter, in this work we have used a recombinantly-produced P. chabaudi ATP2, PcATP2, to gain insights into the function and structural organization of this essential transporter. Our work demonstrates that PcATP2 heterodimerizes with two of the three Plasmodium-encoded Cdc50 proteins: PcCdc50B and PcCdc50A, indispensable partners for most P4-ATPases. Moreover, the purified PcATP2/PcCdc50B complex catalyses ATP hydrolysis in the presence of phospholipids containing either phosphatidylserine, phosphatidylethanolamine or phosphatidylcholine head groups, and that this activity is upregulated by phosphatidylinositol 4-phosphate. Overall, our work provides the first study of the function and quaternary organization of ATP2, a promising antimalarial drug target candidate.

scholarly journals Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

2013 ◽  
Vol 6 (2) ◽  
pp. 112-121 ◽  
Author(s):  
Megan H. Wright ◽  
Barbara Clough ◽  
Mark D. Rackham ◽  
Kaveri Rangachari ◽  
James A. Brannigan ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Drug Target ◽  
Chemical Biology

Reverse Fosmidomycin Derivatives against the Antimalarial Drug Target IspC (Dxr)

2011 ◽  
Vol 54 (19) ◽  
pp. 6796-6802 ◽  
Author(s):  
Christoph T. Behrendt ◽  
Andrea Kunfermann ◽  
Victoria Illarionova ◽  
An Matheeussen ◽  
Miriam K. Pein ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Drug Target

The apicoplast as an antimalarial drug target

2001 ◽  
Vol 4 (3) ◽  
pp. 145-151 ◽  
Author(s):  
Stuart A. Ralph ◽  
Marthe C. D'Ombrain ◽  
Geoffrey I. McFadden
Keyword(s):  
Antimalarial Drug ◽  
Drug Target

scholarly journals Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum is dispensable and not the functional target of putative NDH2 quinolone inhibitors

2018 ◽  
Author(s):  
Hangjun Ke ◽  
Suresh M. Ganesan ◽  
Swati Dass ◽  
Joanne M. Morrisey ◽  
Sovitj Pou ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Nadh Dehydrogenase ◽  
Antimalarial Activity ◽  
Reductase Activity ◽  
Proton Pumping ◽  
Type Ii ◽  
Long Time ◽  
Specific Inhibitors

AbstractThe battle against malaria has been substantially impeded by the recurrence of drug resistance in Plasmodium falciparum, the deadliest human malaria parasite. To counter the problem, novel antimalarial drugs are urgently needed, especially those that target unique pathways of the parasite, since they are less likely to have side effects. The mitochondrial type II NADH dehydrogenase of P. falciparum, PfNDH2 (PF3D7_0915000), has been considered a good prospective antimalarial drug target for over a decade, since malaria parasites lack the conventional multi-subunit NADH dehydrogenase, or Complex I, present in the mammalian mitochondrial electron transport chain (mtETC). Instead, Plasmodium parasites contain a single subunit NDH2, which lacks proton pumping activity and is absent in humans. A significant amount of effort has been expended to develop PfNDH2 specific inhibitors, yet the essentiality of PfNDH2 has not been convincingly verified. Herein, we knocked out PfNDH2 in P. falciparum via a CRISPR/Cas9 mediated approach. Deletion of PfNDH2 does not alter the parasite’s susceptibility to multiple mtETC inhibitors, including atovaquone and ELQ-300. We also show that the antimalarial activity of the fungal NDH2 inhibitor HDQ and its new derivative CK-2-68 is due to inhibition of the parasite cytochrome bc1 complex rather than PfNDH2. These compounds directly inhibit the ubiquinol-cytochrome c reductase activity of the malarial bc1 complex. Our results call into question the validity of PfNDH2 as an antimalarial drug target.ImportanceFor a long time, PfNDH2 has been considered an attractive antimalarial drug target. However, the conclusion that PfNDH2 is essential was based on preliminary and incomplete data. Here we generate a PfNDH2 KO (knockout) parasite in the blood stages of Plasmodium falciparum, showing that the gene is not essential. We also show that previously reported PfNDH2-specific inhibitors kill the parasites primarily via targeting the cytochrome bc1 complex, not PfNDH2. Overall, we provide genetic and biochemical data that help to resolve a long-debated issue in the field regarding the potential of PfNDH2 as an antimalarial drug target.

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