A5000939021- Malaria Research and Control
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Mosquito-borne diseases and control
- Pneumocystis jirovecii pneumonia detection and treatment
- Research on Leishmaniasis Studies
- HIV/AIDS drug development and treatment
- Trypanosoma species research and implications
- Biochemical and Molecular Research
- Metabolomics and Mass Spectrometry Studies
- vaccines and immunoinformatics approaches
- Quinazolinone synthesis and applications
- HIV Research and Treatment
- RNA modifications and cancer
- Electrochemical sensors and biosensors
- RNA and protein synthesis mechanisms
- Multiple Myeloma Research and Treatments
- Glycosylation and Glycoproteins Research
- Parasites and Host Interactions
- Phenothiazines and Benzothiazines Synthesis and Activities
- thermodynamics and calorimetric analyses
- Biochemical and Structural Characterization
Monash University
2016-2024
Australian Regenerative Medicine Institute
2023-2024
University of Basel
2024
Deakin University
2024
Bridge University
2024
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified 5'-sulfamate broad-specificity compound that hijacks range ML901 specific reagent single aaRS in malaria parasite Plasmodium falciparum,...
Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin frontline treatments for malaria, but resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate protein alkylation targets ozonide probes, including an analogue candidate, artefenomel. We greatly expanded list proteins alkylated by identified...
ABSTRACT Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics vitro responses Plasmodium falciparum to new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from region Cambodia genetically matched sensitive) revertant. pulsed-exposure assay format interrogate time...
Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination activity-based protein profiling (ABPP), to demonstrate that peroxide initially target haemoglobin (Hb) digestion pathway kill parasites. Time-dependent metabolomic of ozonide-treated P. falciparum infected red blood cells revealed rapid depletion...
Current best practice for the treatment of malaria relies on short half-life artemisinins that are failing against emerging Kelch 13 mutant parasite strains. Here, we introduce a liposome-like self-assembly dimeric artesunate glycerophosphocholine conjugate (dAPC-S) as an amphiphilic prodrug short-lived antimalarial drug, dihydroartemisinin (DHA), with enhanced killing artemisinin-resistant parasites. Cryo-electron microscopy (cryoEM) images and dynamic light scattering (DLS) technique show...
New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive target using selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition recombinant falciparum ( Pf A-M1) and vivax Pv metalloaminopeptidases, with selectivity over other human aminopeptidases, displayed excellent in vitro activity no significant host...
To combat the global burden of malaria, development new drugs to replace or complement current therapies is urgently required. Here, we show that compound
The peroxide bond of the artemisinins inspired development a class fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as ozonides. Similar to artemisinins, heme-mediated degradation ozonides generates highly reactive radical species that are thought mediate parasite killing by damaging critical biomolecules. We examined relationship between dependent and antimalarial activity for two ozonides, OZ277 (arterolane) OZ439 (artefenomel), using combination in vitro drug...
The mechanism of action ozonide antimalarials involves activation by intraparasitic iron and the formation highly reactive carbon-centered radicals that alkylate malaria parasite proteins. Given free heme is generally thought to be source responsible for its likely close proximity activated drug, we investigated as a possible molecular target ozonides. Using an extraction method optimized solubilization heme, untargeted LC-MS analysis ozonide-treated parasites identified several regioisomers...
To contribute to the global effort develop new antimalarial therapies, we previously disclosed initial findings on optimization of dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here report refining aqueous solubility and metabolic stability improve pharmacokinetic profile consequently in vivo efficacy. We show incorporation heterocycle systems 8-position scaffold was found provide greatest attainable balance between parasite activity, solubility, stability. Optimized analogs,...
<title>Abstract</title> New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria resistance. Here, we describe the multi-omic chemical validation of <italic>Plasmodium </italic>M1 alanyl metalloaminopeptidase as an attractive target using selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition recombinant falciparum</italic> (<italic>Pf</italic>A-M1) and vivax</italic> (<italic>Pv</italic>-M1) M1 metalloaminopeptidases, with...
New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive target using selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition recombinant falciparum ( Pf A-M1) and vivax Pv -M1) metalloaminopeptidases, with selectivity over other human aminopeptidases, displayed excellent in vitro activity no significant...
<title>Abstract</title> New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria resistance. Here, we describe the multi-omic chemical validation of <italic>Plasmodium </italic>M1 alanyl metalloaminopeptidase as an attractive target using selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition recombinant falciparum</italic> (<italic>Pf</italic>A-M1) and vivax</italic> (<italic>Pv</italic>A-M1) M1 metalloaminopeptidases, with...
New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive target using selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition recombinant falciparum ( Pf A-M1) and vivax Pv metalloaminopeptidases, with selectivity over other human aminopeptidases, displayed excellent in vitro activity no significant host...
<title>Abstract</title> New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria resistance. Here, we describe the multi-omic chemical validation of <italic>Plasmodium </italic>M1 alanyl metalloaminopeptidase as an attractive target using selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition recombinant falciparum</italic> (<italic>Pf</italic>A-M1) and vivax</italic> (<italic>Pv</italic>A-M1) M1 metalloaminopeptidases, with...