A5068768589- Malaria Research and Control
- Computational Drug Discovery Methods
- Research on Leishmaniasis Studies
- HIV/AIDS drug development and treatment
- Glycosylation and Glycoproteins Research
- Mosquito-borne diseases and control
- Ubiquitin and proteasome pathways
- Trypanosoma species research and implications
- HIV Research and Treatment
- Peripheral Nerve Disorders
- RNA and protein synthesis mechanisms
- Phenothiazines and Benzothiazines Synthesis and Activities
- Endoplasmic Reticulum Stress and Disease
- Orthopedic Surgery and Rehabilitation
- Dupuytren's Contracture and Treatments
- Insect and Pesticide Research
- Antibiotic Resistance in Bacteria
- Peptidase Inhibition and Analysis
Xiangya Hospital Central South University
2025
Central South University
2025
University of California, San Diego
2021-2023
The University of Melbourne
2015-2022
Abstract Artemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden in Plasmodium falciparum infections, antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity ARTs emerging, making it critically important understand mechanism of action ARTs. Here we demonstrate that dihydroartemisinin (DHA), clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, compromising...
Increased tolerance of Plasmodium falciparum to front-line artemisinin antimalarials (ARTs) is associated with mutations in Kelch13 (K13), although the precise role K13 remains unclear. Here, we show that result decreased expression this protein, while mislocalization mimics resistance-conferring mutations, pinpointing partial loss function as relevant molecular event. K13-GFP ∼170 nm diameter doughnut-shaped structures at parasite periphery, consistent location and dimensions cytostomes....
Current first-line artemisinin antimalarials are threatened by the emergence of resistant Plasmodium falciparum. Decreased sensitivity is evident in initial (early ring) stage intraerythrocytic development, making it critical to understand action artemisinins at this stage. We examined roles iron and haem activation early rings using chelators a specific haemoglobinase inhibitor (E64d). Quantitative modelling antagonism accounted for its complex dependence on chemical features drug exposure...
Development of antimalarial compounds into clinical candidates remains costly and arduous without detailed knowledge the target. As resistance increases treatment options at various stages disease are limited, it is critical to identify multistage drug targets that readily interrogated in biochemical assays. Whole-genome sequencing 18 parasite clones evolved using thienopyrimidine with submicromolar, rapid-killing, pan-life cycle antiparasitic activity showed all had acquired mutations P....
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...
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...
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...