Plasmodium falciparum FIKK9.1 is a monomeric serine–threonine protein kinase with features to exploit as a drug target

2021 ◽  
Author(s):  
Anil Kumar D. ◽  
Deepti Shrivastava ◽  
Amogh A. Sahasrabuddhe ◽  
Saman Habib ◽  
Vishal Trivedi
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Drug Target

scholarly journals Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target

Science ◽  
2019 ◽  
Vol 365 (6456) ◽  
pp. eaau1682 ◽  
Author(s):  
Mahmood M. Alam ◽  
Ana Sanchez-Azqueta ◽  
Omar Janha ◽  
Erika L. Flannery ◽  
Amit Mahindra ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Rna Splicing ◽  
Drug Target ◽  
Selective Inhibitor ◽  
Molecular Pathways ◽  
Life Stages ◽  
Next Generation ◽  
Down Regulation ◽  
Transmission Blocking

The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase PfCLK3, which we used in combination with chemogenetics to validate PfCLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for PfCLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of PfCLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi. Hence, our data establish PfCLK3 as a target for drugs, with the potential to offer a cure—to be prophylactic and transmission blocking in malaria.

scholarly journals Plasmodium falciparum cGMP-Dependent Protein Kinase – A Novel Chemotherapeutic Target

2021 ◽  
Vol 11 ◽  
Author(s):  
David Rotella ◽  
John Siekierka ◽  
Purnima Bhanot
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Drug Target ◽  
Dependent Protein Kinase ◽  
The Past ◽  
Cgmp Dependent Protein Kinase ◽  
Cgmp Signaling ◽  
Erythrocytic Cycle ◽  
Dependent Protein ◽  
Primary Effector

The primary effector of cGMP signaling in Plasmodium is the cGMP-dependent protein kinase (PKG). Work in human-infective Plasmodium falciparum and rodent-infective Plasmodium berghei has provided biological validation of P. falciparum PKG (PfPKG) as a drug target for treating and/or protecting against malaria. PfPKG is essential in the asexual erythrocytic and sexual cycles as well as the pre-erythrocytic cycle. Medicinal chemistry efforts, both target-based and phenotype-based, have targeted PfPKG in the past few years. This review provides a brief overview of their results and challenges.

scholarly journals Development of Potent and Selective PfCLK3 Inhibitors Based on GSK-TCMDC151 as a New Class of Antimalarials

2019 ◽  
Author(s):  
Amit Mahindra ◽  
Omar Janha ◽  
Kopano Mapesa ◽  
Ana Sanchez-Azqueta ◽  
Mahmood M. Alam ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Recombinant Protein ◽  
Mechanism Of Action ◽  
Rna Splicing ◽  
Drug Target ◽  
Critical Role ◽  
Malarial Parasite ◽  
Lead Compound ◽  
New Class

<p>The kinase <i>Pf</i>CLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage <i>Plasmodium falciparum</i>. We recently validated <i>Pf</i>CLK3 as a drug target in malaria that offers prophylactic, transmission blocking and curative potential. Herein we describe the synthesis of our initial hit TCMDC-135051 <b>1</b>and efforts to establish a SAR with a 7-azaindole-based series. A total of 14 analogues were assessed in a TR-FRET assay against the full recombinant protein kinase <i>Pf</i>CLK3 and 10 were further assessed in parasites 3D7 (chloroquine sensitive) strains of <i>P. falciparum</i>. SAR relating to rings A and B was established. These data suggest that TCMDC-135051 <b>1</b>is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting <i>Pf</i>CLK3.</p>

scholarly journals Development of Potent and Selective PfCLK3 Inhibitors Based on GSK-TCMDC151 as a New Class of Antimalarials

2019 ◽  
Author(s):  
Amit Mahindra ◽  
Omar Janha ◽  
Kopano Mapesa ◽  
Ana Sanchez-Azqueta ◽  
Mahmood M. Alam ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Recombinant Protein ◽  
Mechanism Of Action ◽  
Rna Splicing ◽  
Drug Target ◽  
Critical Role ◽  
Malarial Parasite ◽  
Lead Compound ◽  
New Class

<p>The kinase <i>Pf</i>CLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage <i>Plasmodium falciparum</i>. We recently validated <i>Pf</i>CLK3 as a drug target in malaria that offers prophylactic, transmission blocking and curative potential. Herein we describe the synthesis of our initial hit TCMDC-135051 <b>1</b>and efforts to establish a SAR with a 7-azaindole-based series. A total of 14 analogues were assessed in a TR-FRET assay against the full recombinant protein kinase <i>Pf</i>CLK3 and 10 were further assessed in parasites 3D7 (chloroquine sensitive) strains of <i>P. falciparum</i>. SAR relating to rings A and B was established. These data suggest that TCMDC-135051 <b>1</b>is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting <i>Pf</i>CLK3.</p>

Dynamical Basis of Allosteric Activation for the Plasmodium falciparum Protein Kinase G

2021 ◽  
Author(s):  
Jinfeng Huang ◽  
Jung Ah Byun ◽  
Bryan VanSchouwen ◽  
Philipp Henning ◽  
Friedrich W. Herberg ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Protein Kinase G ◽  
Allosteric Activation ◽  
Falciparum Protein

scholarly journals Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

RSC Advances ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 2453-2461
Author(s):  
Min-Che Tung ◽  
Keng-Chang Tsai ◽  
Kit-Man Fung ◽  
Ming-Jaw Don ◽  
Tien-Sheng Tseng
Keyword(s):  
Natural Products ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Mode Of Action ◽  
Drug Target ◽  
Receptor Protein ◽  
Inflammatory Disorder ◽  
Spleen Tyrosine Kinase ◽  
Structure Activity Relationships ◽  
Structure Activity

The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications.

The hexose transporter of Plasmodium falciparum is a worthy drug target

Acta Tropica ◽  
2004 ◽  
Vol 89 (3) ◽  
pp. 371-374 ◽  
Author(s):  
Thierry Joët ◽  
Sanjeev Krishna
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Target ◽  
Hexose Transporter
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