Protein Arginine Methyltransferase Inhibitors Target Multiple Stages of Plasmodium falciparum Parasites In Vitro

TY - JOUR

T1 - Protein Arginine Methyltransferase Inhibitors Target Multiple Stages of Plasmodium falciparum Parasites In Vitro

AU - Opperman, Daniel

AU - Rabie, Tayla

AU - Maré, Marché

AU - Naude, Mariska

AU - van der Watt, Mariette

AU - Thibaud, Jessica L.

AU - Shannon, Megan

AU - Sanders, Nicole

AU - Bolscher, Judith M.

AU - van der Laak, Rianne

AU - Willemsen, Rowy

AU - Bronkhorst, Alfred

AU - Boonyalai, Nonlawat

AU - Lee, Marcus C.S.

AU - Birkholtz, Lyn Marié

N1 - Publisher Copyright: © 2026 The Authors. Published by American Chemical Society

PY - 2026/4/10

Y1 - 2026/4/10

N2 - The ongoing rise in antimalarial drug resistance underscores the urgent need for new drug candidates that specifically target novel mechanisms. Malaria parasites employ various epigenetic strategies to regulate gene expression throughout their complex life cycle, with histone lysine acetylation and methylation being well-studied and targeted by new antiplasmodials. By contrast, arginine methylation remains poorly explored. Plasmodium falciparum possesses three protein arginine methyltransferases (PRMTs) that maintain a unique and combinatorial histone arginine methylation landscape. Here, we present a chemical repositioning strategy to evaluate the efficacy of known PRMT inhibitors against malaria parasites. We identified a potent compound, TC-E 5003, which is active across multiple stages of parasite development. PfPRMT1 was proposed as the most likely target of TC-E 5003, with a distinct structure–activity relationship demonstrated by TC-E 5003 analogs from a hit expansion campaign. The chemotype exhibits a clear pharmacophore that elucidates the compound’s mechanism of action. Overall, these findings open a new pathway for identifying multistage active antiplasmodial candidates targeting a novel protein family in P. falciparum.

AB - The ongoing rise in antimalarial drug resistance underscores the urgent need for new drug candidates that specifically target novel mechanisms. Malaria parasites employ various epigenetic strategies to regulate gene expression throughout their complex life cycle, with histone lysine acetylation and methylation being well-studied and targeted by new antiplasmodials. By contrast, arginine methylation remains poorly explored. Plasmodium falciparum possesses three protein arginine methyltransferases (PRMTs) that maintain a unique and combinatorial histone arginine methylation landscape. Here, we present a chemical repositioning strategy to evaluate the efficacy of known PRMT inhibitors against malaria parasites. We identified a potent compound, TC-E 5003, which is active across multiple stages of parasite development. PfPRMT1 was proposed as the most likely target of TC-E 5003, with a distinct structure–activity relationship demonstrated by TC-E 5003 analogs from a hit expansion campaign. The chemotype exhibits a clear pharmacophore that elucidates the compound’s mechanism of action. Overall, these findings open a new pathway for identifying multistage active antiplasmodial candidates targeting a novel protein family in P. falciparum.

KW - arginine methylation

KW - Plasmodium falciparum

KW - PRMT

KW - PRMT inhibitors

UR - https://www.scopus.com/pages/publications/105035550440

U2 - 10.1021/acsinfecdis.6c00182

DO - 10.1021/acsinfecdis.6c00182

M3 - Article

C2 - 41914674

AN - SCOPUS:105035550440

SN - 2373-8227

VL - 12

SP - 1455

EP - 1468

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 4

ER -