A5068725892- Malaria Research and Control
- HIV/AIDS drug development and treatment
- Mosquito-borne diseases and control
- Biochemical and Molecular Research
- Neurological diseases and metabolism
- Fungal Plant Pathogen Control
- X-ray Diffraction in Crystallography
- HIV Research and Treatment
- Synthesis and biological activity
- Click Chemistry and Applications
- Crystallization and Solubility Studies
- Synthesis and Biological Evaluation
- Hepatitis C virus research
- Metabolomics and Mass Spectrometry Studies
- Vitamin K Research Studies
- Chemical Synthesis and Analysis
- Antifungal resistance and susceptibility
Pennsylvania State University
2019-2024
We identify the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as a druggable target, using genetic and chemical validation. In vitro evolution of resistance with two antiplasmodial drug-like compounds (MMV019721 MMV084978) selects for mutations in PfAcAS. Metabolic profiling compound-treated parasites reveals changes acetyl-CoA levels both compounds. Genome editing confirms that PfAcAS are sufficient to confer resistance. Knockdown studies demonstrate is essential asexual...
Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties in vivo efficacy humanized mouse model Plasmodium falciparum infection. The compound shows single digit nanomolar vitro activity against P. vivax clinical isolates, potently blocks transmission Anopheles...
The mitochondrion of malaria parasites contains several clinically validated drug targets. Within Plasmodium spp., the causative agents malaria, mitochondrial DNA (mtDNA) is only 6 kb long, being smallest genome among all eukaryotes. mtDNA encodes three proteins electron transport chain and ∼27 small, fragmented rRNA genes having lengths 22–195 nucleotides. fragments are thought to form a ribosome (mitoribosome), together with ribosomal imported from cytosol. mitoribosome falciparum...
Coenzyme A (CoA) biosynthesis is an excellent target for antimalarial intervention. While most studies have focused on the use of CoA to produce acetyl-CoA in apicoplast and cytosol malaria parasites, mitochondrial production less well understood. In current study, we performed metabolite-labeling experiments measure endogenous metabolites Plasmodium falciparum lines with genetic deletions affecting dehydrogenase activity. Our results show that mitochondrion required cellular identify a...
ABSTRACT The mitochondrion of the deadliest human malaria parasite, Plasmodium falciparum, is an essential source cellular acetyl-CoA during asexual blood-stage parasite life cycle. Blocking mitochondrial synthesis leads to a hypoacetylated proteome and death. We previously determined that primarily synthesized from glucose-derived pyruvate by α-ketoacid dehydrogenases. Here, we asked if inhibiting import glycolytic across inner membrane would affect production and, thus, could be potential...
Abstract Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as first-in-class acetyl-CoA synthetase (ACS) inhibitor to enter preclinical development. Our studies demonstrated attractive drug-like properties in vivo efficacy humanized mouse model Plasmodium falciparum infection. The compound showed exceptional vitro activity against P. vivax clinical isolates, potently blocked transmission Anopheles...
ABSTRACT The mitochondrion of malaria parasites contains clinically validated drug targets. Within Plasmodium spp ., the mitochondrial DNA (mtDNA) is only 6 kb long, being smallest genome among all eukaryotes. mtDNA encodes three proteins electron transport chain and ∼ 27 small, fragmented rRNA genes in length 22-195 nucleotides. fragments are thought to form a ribosome (mitoribosome), together with ribosomal imported from cytosol. mitoribosome falciparum has been shown be essential for...
Abstract Coenzyme A (CoA) biosynthesis is an excellent target for antimalarial intervention. While most studies have focused on the use of CoA to produce acetyl-CoA in apicoplast and cytosol malaria parasites, mitochondrial production less well understood. In current study, we performed metabolite labeling experiments measure endogenous metabolites Plasmodium falciparum lines with genetic deletions affecting dehydrogenase activity. Our results show that essential parasite growth identify a...