A5030009340- Malaria Research and Control
- Computational Drug Discovery Methods
- Synthesis and Catalytic Reactions
- HIV/AIDS drug development and treatment
- Mosquito-borne diseases and control
- Synthesis and biological activity
- Astrophysical Phenomena and Observations
- Phenothiazines and Benzothiazines Synthesis and Activities
- Trypanosoma species research and implications
- Cancer therapeutics and mechanisms
- Drug Transport and Resistance Mechanisms
- Synthesis and Biological Evaluation
- Drug-Induced Hepatotoxicity and Protection
- Parasitic Diseases Research and Treatment
- Research on Leishmaniasis Studies
- Pharmacogenetics and Drug Metabolism
- Biochemical and Molecular Research
- Click Chemistry and Applications
- Synthesis and Characterization of Heterocyclic Compounds
- Traditional and Medicinal Uses of Annonaceae
- Scientific Measurement and Uncertainty Evaluation
- Insect symbiosis and bacterial influences
- Bioactive Compounds and Antitumor Agents
- Chemical Synthesis and Analysis
- Synthesis and Reactions of Organic Compounds
University of Exeter
2023-2025
University of Liverpool
2015-2024
Liverpool School of Tropical Medicine
2003-2020
Liverpool Hospital
2015-2019
Belfast Health and Social Care Trust
2014
University of Lisbon
2013
GlaxoSmithKline (United Kingdom)
2008-2009
Imperial College London
2004-2008
Charles Sturt University
2007-2008
Mid Sweden University
2008
We present an analysis of the X-ray spectra a sample 37 observations 26 Seyfert galaxies observed by XMM–Newton in order to characterize their iron Kα emission. All objects show evidence for line emission 6–7 keV band. A narrow ‘core’ at 6.4 is seen almost universally spectra, and we model this using neutral Compton reflection component, assumed be associated with distant, optically thick material such as molecular torus. Once this, absorption zone ionized gas sight accounted for, less than...
Significance The mechanism of action the artemisinin (ART) class antimalarial drugs, most important drug in use today, remains controversial, despite more than three decades intensive research. We have developed an unbiased chemical proteomic approach using a suite ART activity-based protein profiling probes to identify proteins within malaria parasite that are alkylated by ART, including involved glycolysis, hemoglobin metabolism, and redox defense. data point pleiotropic for this offer...
Abstract The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. main protease of (M pro ), critical for viral replication, is a key target therapeutic development. An organoselenium drug called ebselen been demonstrated have potent M inhibition and antiviral activity. We examined the binding modes its derivative in via high resolution co-crystallography investigated their chemical reactivity mass spectrometry. Stronger than ability rescue infected cells were observed...
Evidence is reviewed elucidating the mechanism of iron-induced triggering antimalarial trioxanes. As prodrugs, trioxanes undergo homolytic, inner-sphere, reductive cleavage by ferrous iron to form sequentially oxy radicals, carbon high-valent iron−oxo species, epoxides, aldehydes, and dicarbonyl compounds. One or more these reactive intermediates neutral alkylating agents likely kill malaria parasites. Several new, orally active peroxides have been designed rationally based on this...
Artemisinin and its derivatives are currently recommended as first-line antimalarials in regions where Plasmodium falciparum is resistant to traditional drugs. The cytotoxic activity of these endoperoxides toward rapidly dividing human carcinoma cells cell lines has been reported, it hypothesized that activation the endoperoxide bridge by an iron(II) species, form C-centered radicals, essential for cytotoxicity. studies described here have utilized artemisinin derivatives,...
The artemisinin compounds are the frontline drugs for treatment of drug-resistant malaria. They selectively cytotoxic to mammalian cancer cell lines and have been implicated as neurotoxic embryotoxic in animal studies. endoperoxide functional group is both pharmacophore toxicophore, but proposed chemical mechanisms targets cytotoxicity remain unclear. In this study we used models quantitative drug metabolite analysis define role mitochondrion cellular heme molecular death induced by...
There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance all existing classes, including the artemisinins, has been reported during their clinical use. A failure generate antimalarials that circumvent current challenges will contribute a resurgence in disease which would represent global health emergency. Here we present unique generation quinolone lead dual mechanism against two respiratory...
ObjectivesArtemisinin and artemisinin semi-synthetic derivatives (collectively known as endoperoxides) are first-line antimalarials for the treatment of uncomplicated severe malaria. Endoperoxides display very fast killing rates generally recalcitrant to parasite resistance development. These key pharmacodynamic features a result complex mechanism action, details which lack consensus. Here, we report on primary physiological events leading death.
Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages Plasmodium falciparum. The activity PQ depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. requires hepatic metabolism to exert gametocyte stages. modest parasite gametocytes; however, potency...
Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival fecundity, making Wolbachia a promising therapeutic target. Here we perform high-throughput screen of AstraZeneca's 1.3 million in-house compound library identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the...
Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute pathogenicity a reduced ability complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers characteristic large insoluble aggregates within motor system cells. Here we report that...
In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism action. This is important since will influence cross-resistance risks between different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial were able to alkylate protein target(s) within asexual erythrocytic stage Plasmodium...
Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration clinical setting. Next-generation snakebite are being widely investigated the aim improve efficacy, safety. In recent years small molecule drugs shown considerable promise indication, oral bioavailability...
We have investigated the contribution of drug accumulation and inhibition heme polymerization to in vitro activities a series antimalarial drugs. Only those compounds exhibiting structural relatedness quinolines inhibited polymerization. could find no direct correlation between activity against chloroquine-susceptible or chloroquine-resistant isolates either cellular for drugs studied. However, isolate but not showed significant with when was normalized extent accumulation. The importance...
Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which bind cellular macromolecules initiate hypersensitivity reactions. We proposed interchange 3' hydroxyl 4' Mannich side-chain function would provide new series analogues cannot form toxic metabolites via cytochrome P450-mediated...