Targeting Aurora Kinases as Essential Cell‐Cycle Regulators to Deliver Multi‐Stage Antimalarials Against <i>Plasmodium Falciparum</i>
Abstract
Abstract Kinases play critical roles in the development and adaptation of Plasmodium falciparum and present novel opportunities for chemotherapeutic intervention. Mitotic kinases that regulate the proliferation of the parasites by controlling nuclear division, segregation, and cytokinesis. We evaluated the potential of human Aurora kinase (Aur) inhibitors to prevent P. falciparum development by targeting members of the Aurora‐related kinase (Ark) family in this parasite. Several human AurB inhibitors exhibited multistage potency (< 250 nM) against all proliferative stages of parasite development, including asexual blood stages, liver schizonts, and male gametes. The most potent compounds, hesperadin, TAE684, and AT83, exhibited > 1000x selectivity towards the parasite. Importantly, we identified Pf Ark1 as the principal vulnerable Ark family member, with specific inhibition of Pf Ark1 as the primary target for hesperadin. Hesperadin's whole‐cell and protein activity validates it as a unique Pf Ark1 tool compound. Inhibition of Pf Ark1 results in the parasite's inability to complete mitotic processes, presenting with unsegregated, multi‐lobed nuclei caused by aberrant microtubule organization. This suggests Pf Ark1 is the main Aur mitotic kinase in proliferative stages of Plasmodium , characterized by bifunctional AurA and B activity. This paves the way for drug‐discovery campaigns based on hesperadin targeting Pf Ark1.
Article Details
Authors (24)
Henrico Langeveld
Department of Biochemistry, Genetics and Microbiology Hatfield Pretoria 0028 South Africa
Keletso Maepa
South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine University of Cape Town Rondebosch, Cape Town 7701 South Africa
Marché Maree
Department of Biochemistry, Genetics and Microbiology Hatfield Pretoria 0028 South Africa
Jessica L. Thibaud
Department of Biochemistry Stellenbosch University Stellenbosch 7602 South Africa
Nicolaas Salomane
Rosie Bridgwater
LSHTM Malaria Centre London School of Hygiene and Tropical Medicine London UK
Mufuliat T. Famodimu
LSHTM Malaria Centre London School of Hygiene and Tropical Medicine London UK
Luiz C. Godoy
Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
Charisse Flerida A. Pasaje
Nonlawat Boonyalai
Division of Biological Chemistry and Drug Discovery Wellcome Centre for Anti‐Infectives Research University of Dundee Dundee UK
Mariana Laureano de Souza
Department of Pediatrics School of Medicine University of California San Diego CA 92093 USA
Justin Fong
Department of Pediatrics School of Medicine University of California San Diego CA 92093 USA
Tayla Rabie
Department of Biochemistry, Genetics and Microbiology Hatfield Pretoria 0028 South Africa
Mariëtte van der Watt
Institute for Sustainable Malaria Control University of Pretoria Hatfield Pretoria 0028 South Africa
Rensu P. Theart
Department of Electrical and Electronic Engineering Stellenbosch University Stellenbosch 7602 South Africa
Sonja Ghidelli‐Disse
Cellzome GmbH, GSK Company Heidelberg Germany
Jacquin C. Niles
Marcus C. S. Lee
Elizabeth A. Winzeler
Michael J. Delves
LSHTM Malaria Centre London School of Hygiene and Tropical Medicine London UK
Kelly Chibale
Kathryn J. Wicht
South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine University of Cape Town Rondebosch, Cape Town 7701 South Africa
Lauren B. Coulson
South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine University of Cape Town Rondebosch, Cape Town 7701 South Africa
Lyn‐Marié Birkholtz
Department of Biochemistry, Genetics and Microbiology Hatfield Pretoria 0028 South Africa