Human Aurora kinase inhibitor Hesperadin reveals epistatic interaction between Plasmodium falciparum PfArk1 and PfNek1 kinases.

Communications Biology
Belinda J MorahanJose F Garcia-Bustos

Abstract

Mitosis has been validated by numerous anti-cancer drugs as being a druggable process, and selective inhibition of parasite proliferation provides an obvious opportunity for therapeutic intervention against malaria. Mitosis is controlled through the interplay between several protein kinases and phosphatases. We show here that inhibitors of human mitotic kinases belonging to the Aurora family inhibit P. falciparum proliferation in vitro with various potencies, and that a genetic selection for mutant parasites resistant to one of the drugs, Hesperadin, identifies a resistance mechanism mediated by a member of a different kinase family, PfNek1 (PF3D7_1228300). Intriguingly, loss of PfNek1 catalytic activity provides protection against drug action. This points to an undescribed functional interaction between Ark and Nek kinases and shows that existing inhibitors can be used to validate additional essential and druggable kinase functions in the parasite.

References

Jun 8, 2001·Parasitology·S Paget-McNicol, A Saul
Jul 15, 2003·Molecular Biology of the Cell·Alison J Faragher, Andrew M Fry
Aug 20, 2003·Molecular Biology of the Cell·Reiko HondaErich A Nigg
Nov 20, 2003·Nature Reviews. Molecular Cell Biology·Mar Carmena, William C Earnshaw
Mar 17, 2004·Biochimica Et Biophysica Acta·Christian Doerig
May 4, 2005·Molecular Cell·Fabio SessaAndrea Musacchio
Jun 23, 2005·The Journal of Biological Chemistry·Luc ReiningerChristian Doerig
Oct 6, 2005·The Journal of Cell Biology·Susanne BaheErich A Nigg
Nov 4, 2005·Nature·Douglas J LaCountRobert E Hughes
Oct 30, 2008·Nucleic Acids Research·Cristina AurrecoecheaHaiming Wang
May 21, 2010·Nature·Francisco-Javier GamoJose F Garcia-Bustos
Oct 13, 2011·Molecular Systems Biology·Fabian SieversDesmond G Higgins
Dec 14, 2011·International Journal for Parasitology·Daniel C LimJeroen P J Saeij
Nov 8, 2012·Journal of Cell Science·Andrew M FryRichard Bayliss
Mar 7, 2013·Biochimica Et Biophysica Acta·Teresa Gil CarvalhoLuc Reininger
May 15, 2013·Nucleic Acids Research·Hamish McWilliamRodrigo Lopez
May 21, 2013·Eukaryotic Cell·Jessica Cruz de LeonNaomi S Morrissette
Aug 10, 2013·Journal of Medicinal Chemistry·Erika L FlanneryElizabeth A Winzeler
Jan 5, 2014·Nature Reviews. Microbiology·Maria E Francia, Boris Striepen
Mar 5, 2014·BMC Bioinformatics·Micah J ManaryElizabeth A Winzeler
Nov 29, 2014·Current Protocols in Bioinformatics·Geraldine A Van der AuweraMark A DePristo
Mar 4, 2015·PLoS Biology·Elena S SuvorovaMichael W White
Aug 21, 2015·Nature Communications·Sehyun KimBrian David Dynlacht
Mar 5, 2016·Journal of Cancer Research and Clinical Oncology·Jonas Cicenas
Jun 12, 2016·Biochimica Et Biophysica Acta·Rudra ChhajerNahid Ali
Jun 1, 2019·Scientific Reports·Bénédicte GnangnonChristine Pierrot

❮ Previous
Next ❯

Citations

Feb 18, 2021·Trends in Parasitology·Jack AdderleyChristian Doerig
Mar 30, 2021·Frontiers in Cellular and Infection Microbiology·Coralie BouletTeresa G Carvalho
May 25, 2021·Frontiers in Cellular and Infection Microbiology·Caroline S SimonJulien Guizetti

❮ Previous
Next ❯

Methods Mentioned

BETA
confocal
flow cytometry
fluorescence microscopy
X-ray
PCR
two-hybrid
transfection
transfections

Software Mentioned

Genome Analysis Toolkit GATK
FlowJo
Clustal Omega
COILS
Graphpad Prism
DiagnoseTargets
ImageJ
GATK
Zeiss ZEN lite blue edition
HaplotypeCaller

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.