Biology subjects

Eck, T.

Publications and source records attributed to Eck, T..

4 recordsLinked to original sources

bioRxiv2025

An orally available PfPKG inhibitor blocks sporozoite infection of the liver

Malaria remains a global health threat exacerbated by emerging resistance to antimalarial therapies and insecticides, climate-driven outbreaks, and limited chemoprotective options. Here, we report the characterization of RUPB-61, the first orally bioavailable inhibitor of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG). RUPB-61 prevents infection by P. falciparum and P. cynomolgi sporozoites, including the formation of hypnozoites by the latter. A single oral dose blocks liver infection by P. berghei sporozoites in vivo, demonstrating efficacy consistent with further development as a once-weekly prophylaxis based on pharmacokinetic modeling. The compound retains activity against field isolates resistant to chloroquine, mefloquine, cycloguanil, sulfadoxine and pyrimethamine, suggesting low likelihood of cross-resistance to existing antimalarials. Structural studies and free energy-based modeling guided-compound design prospectively validated the predictive accuracy of an in silico model of PfPKG interactions with this chemotype. While selectivity profiling identified off-target activity against human kinases, structural modeling provides a clear path for optimization. These results establish PfPKG inhibitors as promising candidates for chemoprevention and support further preclinical development of the RUPB-61 chemotype. Author SummaryMalaria remains a serious global health threat, made worse by growing resistance to existing drugs and the spread of insecticide-resistant mosquitoes. A critical gap in our prevention toolkit is the lack of safe, long-acting oral drugs that stop malaria parasites from infecting the liver - the first and obligatory step of every new infection. Here, we report the characterization of RUPB-61, a compound that blocks an enzyme that the malaria parasite needs to invade and survive in the liver. We show that a single oral dose completely prevents liver infection in mice, and that the compound remains active against parasites that are resistant to several currently used antimalarial drugs. Using X-ray crystallography and computer-based modeling, we determined how RUPB-61 binds to its target in atomic detail, providing a roadmap for designing improved versions. While the compound shows some unwanted interactions with human proteins, our structural data offer clear strategies to solve this challenge. Together, these findings provide a solid foundation for developing a new class of once-weekly oral malaria prevention drugs.

microbiology↗

bioRxiv2021

Discovery of imidazole-based inhibitors of P. falciparum cGMP-dependent protein kinase

The discovery of new targets for treatment of malaria and in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this manuscript presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization and cell-based anti-parasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity and cell-based anti-parasitic activity against multiple Plasmodium species that appears to correlate with in vitro potency.

pharmacology and toxicology↗

bioRxiv2021

Discovery of novel potent, cell-permeable inhibitors of P. falciparum cGMP-dependent protein kinase.

The discovery of new targets for treatment of malaria advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, we recently reported the discovery and optimization of novel, potent isoxazole-based PfPKG inhibitors that lacked any obvious safety warnings. This manuscript presents representative in vitro ADME, hERG characterization and cell-based antiparasitic activity of these PfPKG inhibitors. We also report the discovery and structure-activity relationships of a new series with good potency, low hERG activity and cell-based anti-parasitic activity comparable to a literature standard.

pharmacology and toxicology↗

bioRxiv2021

Characterization of novel competitive inhibitors of P. falciparum cGMP-dependent protein kinase

P. falciparum cGMP-dependent protein kinase (PfPKG) is an enticing anti-malarial drug target. Structurally novel isoxazole-based compounds were shown to be ATP competitive inhibitors of PfPKG. Isoxazoles 3 and 5 had Ki values of 0.7 {+/-} 0.2 and 2.3 {+/-} 0.9 nM, respectively, that are comparable to a known standard, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H pyrrol-3-yl] pyridine (1.4 {+/-} 0.5 nM). They also exhibited excellent selectivity for PfPKG over the human ortholog and the gatekeeper mutant T618Q PfPKG, which mimics the less accessible binding site of the human ortholog. The human orthologs larger binding site volume was predicted to explain the selectivity of the inhibitors for the P. falciparum enzyme. Analogs 4 and 6 were at least 20-fold less potent compared to 3 and 5, suggesting that removing the carbonyl group in 3 or altering the diethylamino moiety in 5 reduced affinity.

biochemistry↗