Keywords

Plasmodium falciparum; antiplasmodial; malaria; cyclin-dependent kinase; CDK; inhibitor

Abstract

Malaria remains a major global health burden with over 282 million cases annually and rising resistance to artemisinin-based combination therapies. Plasmodium falciparum, the most lethal malaria parasite species in humans, relies on tightly regulated cell cycle progression during replication within red blood cells. Cyclin-dependent kinases (CDKs) are central regulators of eukaryotic cell division and transcription, and several CDK-like enzymes in P. falciparum, including Pfmrk and PfPK6, are essential for parasite growth and structurally distinct from human kinases. This study evaluated whether commercially available human CDK inhibitors (CDKIs) targeting cancer pathways could be repurposed as novel antimalarial compounds. A library of 261 CDKIs from MedChemExpress was screened against the chloroquine-resistant PfDd2 strain to identify compounds that inhibit parasite growth. Lead compounds were further characterized through dose-response analysis in both PfDd2 and the chloroquine-sensitive Pf3D7 strain, cytotoxicity assessment in human hepatocellular carcinoma (HepG2) cells to evaluate selectivity, and parasite reduction ratio assays to measure the rate and extent of parasite killing. Kinobead affinity purification-mass spectrometry (AP-MS) and the radioactive in-vitro kinase assay confirmed PfPK6 as a target of RGB-286638, a potent but cytotoxic multitarget inhibitor, truly demonstrating the potential and challenges of broad kinase inhibition. Additional compounds, including NecroIr1 and Ryuvidine, exhibited favorable selectivity indices and promising killing kinetics, though their molecular targets remain to be validated. Collectively, these findings support P. falciparum CDKs as potential antimalarial targets and demonstrate the potential of repurposing human kinase inhibitors, including multitarget compounds, to address drug-resistant malaria.

Thesis Completion Year

2026

Thesis Completion Semester

Spring

Thesis Chair

Chakrabarti, Debopam

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Thesis Discipline

Biomedical Sciences

Language

English

Access Status

Open Access

Length of Campus Access

None

Campus Location

Orlando (Main) Campus

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