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 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 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>

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 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.

Sign in / Sign up

Export Citation Format

Share Document