ArticlePloS one2014
Inhibition of the SR protein-phosphorylating CLK kinases of Plasmodium falciparum impairs blood stage replication and malaria transmission.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments.Molecules (Basel, Switzerland) · 2020Pooled it
- Inhibition of PfCLK3 interferes with malaria parasite RNA splicing and explains the mechanism of action of a new class of antimalarial candidates.Antimicrobial agents and chemotherapy · 2026Article
- Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates.Malaria journal · 2023Article
- Article
- Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of PlasmodialJournal of medicinal chemistry · 2022Article
- Targeting theHeliyon · 2022Review
- Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview.International journal of molecular sciences · 2021Review
- CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer.Scientific reports · 2021Article
- Review
- An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors.Molecules (Basel, Switzerland) · 2020Review
- Development of PotentJournal of medicinal chemistry · 2020Article
- Contribution of introns to the species diversity associated with the apicomplexan parasite, Neospora caninum.Parasitology research · 2020Article
- Development of Chemical Entities Endowed with Potent Fast-Killing Properties againstJournal of medicinal chemistry · 2019Article
- Review
- Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2.Bioorganic & medicinal chemistry · 2018Article
- Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14.ACS chemical biology · 2017Article
- Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation.Cell reports · 2017Article
- Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases.Pathogens (Basel, Switzerland) · 2017Article
- Enzyme Activity Assays for Protein Kinases: Strategies to Identify Active Substrates.Current drug discovery technologies · 2016Review
- A WD40-repeat protein unique to malaria parasites associates with adhesion protein complexes and is crucial for blood stage progeny.Malaria journal · 2015Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 5 institutions in 4 countries.
Funding
Abstract
Cyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified three plasmodial SR proteins, PfSRSF12, PfSFRS4 and PfSF-1, which are predominantly present in the nucleus of blood stage trophozoites, PfSRSF12 and PfSF-1 are further detectable in the nucleus of gametocytes. We found that recombinantly expressed SR proteins comprising the Arginine/Serine (RS)-rich domains were phosphorylated by the four PfCLKs in in vitro kinase assays, while a recombinant PfSF-1 peptide lacking the RS-rich domain was not phosphorylated. Since it was hitherto not possible to knock-out the pfclk genes by conventional gene disruption, we aimed at chemical knock-outs for phenotype analysis. We identified five human CLK inhibitors, belonging to the oxo-β-carbolines and aminopyrimidines, as well as the antiseptic chlorhexidine as PfCLK-targeting compounds. The six inhibitors block P. falciparum blood stage replication in the low micromolar to nanomolar range by preventing the trophozoite-to-schizont transformation. In addition, the inhibitors impair gametocyte maturation and gametogenesis in in vitro assays. The combined data show that the four PfCLKs are involved in phosphorylation of SR proteins with essential functions for the blood and sexual stages of the malaria parasite, thus pointing to the kinases as promising targets for antimalarial and transmission blocking drugs.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.