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

2018 ◽  
Author(s):  
Mahmood M Alam ◽  
Ana Sanchez-Azqueta ◽  
Omar Janha ◽  
Erika L. Flannery ◽  
Amit Mahindra ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Rna Splicing ◽  
Drug Target ◽  
Symptomatic Treatment ◽  
Selective Inhibitor ◽  
Life Stages ◽  
Asexual Blood Stage ◽  
Multi Stage ◽  
Parasite Survival

AbstractThe requirement for next generation anti-malarials to be both curative and transmission blockers necessitate the identification of molecular pathways essential for viability of both asexual and sexual parasite life stages. Here we identify a selective inhibitor to the Plasmodium falciparum protein kinase PfCLK3 which we use in combination with chemogenetics, whole genome sequencing and transcriptomics to validate PfCLK3 as a druggable target acting at multiple parasite life stages. Consistent with the proposed role of PfCLK3 as a regulator of RNA splicing, inhibition results in the down-regulation of >400 genes essential for parasite survival. Through this mechanism, blocking PfCLK3 activity not only results in rapid killing of asexual blood stage parasites but is also effective on sporozoites and gametocytes as well as showing parasiticidal activity in all Plasmodium species tested. Hence, our data establishes PfCLK3 as a target with the potential to deliver both symptomatic treatment and transmission blocking in malaria.

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.

Histamine inhibits atrial myocytic ANP release via H2 receptor-cAMP-protein kinase signaling

2003 ◽  
Vol 285 (2) ◽  
pp. R380-R393 ◽  
Author(s):  
Dan Li ◽  
Jin Fu Wen ◽  
Jing Yu Jin ◽  
Hua Jin ◽  
Hai Sun Ann ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Selective Inhibitor ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Camp Analog ◽  
Induced Changes ◽  
Protein Kinase Signaling ◽  
Dose Dependent ◽  
Rabbit Atria

Changes in cyclic nucleotide production and atrial dynamics have been known to modulate atrial natriuretic peptide (ANP) release. Although cardiac atrium expresses histamine receptors and contains histamine, the role of histamine in the regulation of ANP release has to be defined. The purpose of the present study was to define the effect of histamine on the regulation of ANP release in perfused beating rabbit atria. Histamine decreased ANP release concomitantly with increases in cAMP efflux and atrial dynamics in a concentration-dependent manner. Histamine-induced decrease in ANP release was a function of an increase in cAMP production. Blockade of histamine H2 receptor with cimetidine but not of H1 receptor with triprolidine abolished the responses of histamine. Cell-permeable cAMP analog, 8-Br-cAMP, mimicked the effects of histamine, and the responses were dose-dependent and blocked by a protein kinase A (PKA)-selective inhibitor, KT5720. Nifedipine failed to modulate histamine-induced decrease in ANP release. Protein kinase nonselective inhibitor staurosporine blocked histamine-induced changes in a concentration-dependent manner. KT5720 and RP-adenosine 3′,5′-cyclic monophosphorothioate, another PKA-selective inhibitor, attenuated histamine-induced changes. These results suggest that histamine decreases atrial ANP release by H2 receptor-cAMP signaling via PKA-dependent and -independent pathways.

scholarly journals Activity of epigenetic inhibitors against Plasmodium falciparum asexual and sexual blood stages

2019 ◽  
Author(s):  
Leen Vanheer ◽  
Björn F.C. Kafsack
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Epigenetic Regulation ◽  
Malaria Parasite ◽  
Regulation Of Gene Expression ◽  
Life Stages ◽  
Multi Stage ◽  
Promising Target ◽  
Parasite Survival ◽  
Epigenetic Processes

AbstractRegulation of gene expression by epigenetic processes is critical for malaria parasite survival in multiple life stages. To evaluate the suitability of targeting these pathways we screened 350 epigenetic inhibitors against asexual blood stages and gametocytes of P. falciparum. We observed ≥90% inhibition at 10 µM for 28% of compounds, of which a third retained ≥90% inhibition at 1 µM. These results suggest epigenetic regulation as a promising target for the development of new multi-stage anti-malarials.

scholarly journals Highlighting the Role of Cdk6 Associated MicroRNAs in Cancer Treatment Using In Silico Approaches

2020 ◽  
pp. 1-14
Author(s):  
Sidra Batool ◽  
Muhammad Sibte Hasan Mahmood ◽  
Tiyyaba Furqan ◽  
Sidra Batool
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
In Silico ◽  
Drug Target ◽  
In Silico Analysis ◽  
Kinase Domain ◽  
Protein Kinase Domain ◽  
Over Expression ◽  
Silico Analysis

MicroRNAs (miRNAs) are small non-coding RNA’s that controls the regulation of a gene. Due to the over expression or under expression of miRNAs it leads to cause tumor or any other type of cancers such as, melanoma, lymphoma, cardiovascular issue, breast cancer etc. So, miRNAs can be used as a drug target for cancer therapy. This study aimed to check binding cavities of microRNA's involved in regulation of CDK6 protein. There are 23 different families of miRNAs that are involved in regulation of CDK6. Each family has one or more miRNAs. All these miRNAs are involved in the up regulation or downregulation of a gene, which lead to different type of cancers. All miRNAs of each family docked with mRNA CDK6 protein. After performing in silico analysis of binding interactions of mRNA with miRNAs the results were further refined by their comparison with information regarding their energies, interaction of the mRNA and miRNAs. The results show that all miRNAs lie in Protein Kinase domain, but the residues that lie is different within the families and across the families.

Regulation of taurine transport in rat astrocytes by protein kinase C: role of calcium and calmodulin

1996 ◽  
Vol 270 (4) ◽  
pp. C1022-C1028 ◽  
Author(s):  
G. C. Tchoumkeu-Nzouessa ◽  
G. Rebel
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Selective Inhibitor ◽  
Maximal Velocity ◽  
Beta Alanine ◽  
Kinase C ◽  
Rat Astrocytes ◽  
Dimethyl Amiloride ◽  
Taurine Uptake

Phorbol 12-myristate 13-acetate, a potential stimulator of protein kinase C (PKC), inhibited taurine uptake in rat astrocytes. This effect was mimicked by 1-oleoyl-2-acetyl-sn-glycerol, an endogenous stimulator of PKC, and by r-59949, an inhibitor of diacylglycerol kinase. Maximal inhibition was obtained at microM phorbol 12-myristate 13-acetate (PMA) after 1 h of treatment. This effect was prevented by pretreatment of the cells with chelerythrine, a potent and selective inhibitor of PKC. The transport of beta-alanine, an amino acid that shares the same transporter as taurine, was inhibited to a comparable extent. The effect of PMA was potentiated by cotreatment of the cells with thapsigargin or the Ca2+ ionophore A-23187. However, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N1,N1-tetraacetic acid and verapamil did not prevent the PMA effect. Pretreatment of the cells with calmodulin antagonists W-13 or calmidazolium, prevented the PMA-induced inhibition of taurine uptake. This inhibition was not affected by cycloheximide, actinomycin D, colchicine, or cytochalasin D. The Na(+)-to-Cl(-)-to-taurine coupling ratio was unaffected. Dimethyl amiloride, a selective inhibitor of Na+/H+ antiport, was unable to prevent the effects of PMA. These effects were associated with a decrease in the maximal velocity and an increase in the Michaelis-Menten constant.

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>

The role of protein kinase C in the initial events of platelet activation by thrombin assessed with a selective inhibitor

1993 ◽  
Vol 69 (1) ◽  
pp. 113-124 ◽  
Author(s):  
Mark Geanacopoulos ◽  
Joy Turner ◽  
Kristen E. Bowling ◽  
Scott R. Vandenberg ◽  
Adrian R.L. Gear
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Platelet Activation ◽  
Selective Inhibitor ◽  
Kinase C

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>

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