Targeting Aurora Kinases as Essential Cell‐Cycle Regulators to Deliver Multi‐Stage Antimalarials Against <i>Plasmodium Falciparum</i>
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 PfArk1 as the principal vulnerable Ark family member, with specific inhibition of PfArk1 as the primary target for hesperadin. Hesperadin's whole-cell and protein activity validates it as a unique PfArk1 tool compound. Inhibition of PfArk1 results in the parasite's inability to complete mitotic processes, presenting with unsegregated, multi-lobed nuclei caused by aberrant microtubule organization. This suggests PfArk1 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 PfArk1.
Authors
- Charisse Flerida A. Pasaje (ORCID: https://orcid.org/0000-0002-9780-3680)
- Nonlawat Boonyalai (ORCID: https://orcid.org/0000-0002-9058-0840)
- Henrico Langeveld (ORCID: https://orcid.org/0000-0002-5193-9742)
- Rensu P. Theart (ORCID: https://orcid.org/0000-0003-0508-1690)
- Lauren B. Coulson (ORCID: https://orcid.org/0000-0003-4699-0428)
- Jacquin C. Niles (ORCID: https://orcid.org/0000-0002-6250-8796)
- Mufuliat T. Famodimu
- Luiz C. Godoy (ORCID: https://orcid.org/0000-0001-6981-377X)
- Kelly Chibale (ORCID: https://orcid.org/0000-0002-1327-4727)
- Kathryn J. Wicht (ORCID: https://orcid.org/0000-0001-6145-9956)
- Keletso Maepa
- Nicolaas Salomane (ORCID: https://orcid.org/0000-0002-8803-2538)
- Mariana Laureano de Souza (ORCID: https://orcid.org/0000-0003-1886-3878)
- Jean‐Baptiste Thibaud (ORCID: https://orcid.org/0000-0002-0824-6465)
- Michael J. Delves (ORCID: https://orcid.org/0000-0001-8526-4782)
- Mariëtte van der Watt (ORCID: https://orcid.org/0000-0002-9933-8647)
- Elizabeth A. Winzeler (ORCID: https://orcid.org/0000-0002-4049-2113)
- Lyn‐Marié Birkholtz (ORCID: https://orcid.org/0000-0001-5888-2905)
- Sonja Ghidelli‐Disse (ORCID: https://orcid.org/0000-0002-7735-9746)
- Lee M (ORCID: https://orcid.org/0000-0002-4973-0915)
- Jim Fong
- Tayla Rabie
- Marché Maree
- Rosie Bridgwater (ORCID: https://orcid.org/0009-0001-8862-5413)
Institutions
- South African Medical Research Council (ZA)
- University of Cape Town (ZA)
- University of Dundee (GB)
- Stellenbosch University (ZA)
- University of California San Diego (US)
- London School of Hygiene & Tropical Medicine (GB)
- Wellcome Centre for Anti-Infectives Research (GB)
- Heidelberg Engineering (Germany) (DE)
- Massachusetts Institute of Technology (US)
- University of Pretoria (ZA)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1002/anie.202518493
- Citations
- 1
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 1.15
Funders
- National Research Foundation
- South African Medical Research Council
- University of Pretoria
- University of Adelaide
- Medicines for Malaria Venture
- Medical Research Council