Biology subjects

Kooij, T. W.

Publications and source records attributed to Kooij, T. W..

4 recordsLinked to original sources

bioRxiv2025

Structure of endogenous Pfs230:Pfs48/45 in complex with potent malaria transmission-blocking antibodies

The Pfs230:Pfs48/45 complex forms the basis for leading malaria transmission-blocking vaccine candidates, yet li]le is known about its molecular assembly. Here, we used cryogenic electron microscopy to elucidate the structure of the endogenous Pfs230:Pfs48/45 complex bound to six potent transmission-blocking antibodies. Pfs230 consists of multiple domain clusters rigidified by interactions mediated through insertion domains. Membrane-anchored Pfs48/45 forms a disc-like structure and interacts with a short C-terminal peptide on Pfs230 that is critical for Pfs230 membrane-retention in vivo. Interestingly, membrane retention through this interaction is not essential for transmission to mosquitoes, suggesting that complex disruption is not a mode of action for transmission-blocking antibodies. Analyses of Pfs48/45-and Pfs230-targeted antibodies identify conserved epitopes on the Pfs230:Pfs48/45 complex and provides a structural paradigm for complement-dependent activity of Pfs230-targeting antibodies. Altogether, the antibody-bound Pfs230:Pfs48/45 structure presented improves our molecular understanding of this biological complex, informing the development of next-generation Plasmodium falciparum transmission-blocking interventions.

molecular biology↗

bioRxiv2021

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (ACS) inhibitor to enter preclinical development. Our studies demonstrated attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound showed exceptional in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocked P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identified ACS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. MMV693183 was well adsorbed after oral administration in mice, rats and dogs. Pharmacokinetic - pharmacodynamic modelling predicted that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. In conclusion, the ACS-targeting compound MMV693183 represents a promising addition to the portfolio of antimalarials in (pre)clinical development with a novel mode of action for the treatment of malaria and blocking transmission.

microbiology↗

bioRxiv2018

Antimalarial pantothenamide metabolites target acetyl-CoA synthesis in Plasmodium falciparum

Malaria eradication is critically dependent on novel drugs that target resistant Plasmodium parasites and block transmission of the disease. Here we report the discovery of potent pantothenamide bioisosteres that are active against blood-stage P. falciparum and also block onward mosquito transmission. These compounds are resistant to degradation by serum pantetheinases, show favorable pharmacokinetic properties and clear parasites in a humanized rodent infection model. Metabolomics revealed that CoA biosynthetic enzymes convert pantothenamides into drug-conjugates that interfere with parasite acetyl-CoA anabolism. In vitro generated resistant parasites showed mutations in acetyl-CoA synthetase and acyl-CoA synthetase 11, confirming the key roles of these enzymes in the sensitivity to pantothenamides. These new pantothenamides provide a promising class of antimalarial drugs with a unique mode of action.\n\nOne sentence summaryPantothenamides form antimetabolites that interfere with acetyl-CoA metabolism in the human malaria parasite Plasmodium falciparum

pharmacology and toxicology↗

bioRxiv2017

Probabilistic data integration identifies reliable gametocyte-specific proteins and transcripts in malaria parasites

Plasmodium gametocytes are the sexual forms of the malaria parasite essential for transmission to mosquitoes. To better understand how gametocytes differ from asexual blood-stage parasites, we performed a systematic analysis of available omics data for P. falciparum and other Plasmodium species. 18 transcriptomic and proteomic data sets were evaluated for the presence of curated \"gold standards\" of 41 gametocyte-specific versus 46 non-gametocyte genes and integrated using Bayesian probabilities, resulting in gametocyte-specificity scores for all P. falciparum genes.\n\nTo illustrate the utility of the gametocyte score, we explored newly predicted gametocyte-specific genes as potential biomarkers of gametocyte carriage and exposure. We analyzed the humoral immune response in field samples against 30 novel gametocyte-specific antigens and found five antigens to be differentially recognized by gametocyte carriers as compared to malaria-infected individuals without detectable gametocytes. We also validated the gametocyte-specificity of 15 identified gametocyte transcripts on culture material and samples from naturally infected individuals, resulting in eight transcripts that were >1000-fold higher expressed in gametocytes compared to asexual parasites and whose transcript abundance allowed gametocyte detection in naturally infected individuals. Our integrated genome-wide gametocyte-specificity scores provide a comprehensive resource to identify targets and monitor P. falciparum gametocytemia.

microbiology↗