A5042851900- Malaria Research and Control
- Research on Leishmaniasis Studies
- Computational Drug Discovery Methods
- HIV/AIDS drug development and treatment
- Trypanosoma species research and implications
- Drug Transport and Resistance Mechanisms
- RNA and protein synthesis mechanisms
- Neurological diseases and metabolism
- Complement system in diseases
- Invertebrate Immune Response Mechanisms
- Ubiquitin and proteasome pathways
- Vitamin K Research Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Crystallization and Solubility Studies
- Synthesis and biological activity
- Biochemical and Molecular Research
- Mosquito-borne diseases and control
- RNA modifications and cancer
- Quinazolinone synthesis and applications
Imperial College London
2020-2025
National Health Laboratory Service
2017-2018
University of the Witwatersrand
2016-2018
University of Pretoria
2015
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,...
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 development of new antimalarials is required because the threat resistance to current antimalarial therapies. To discover chemotypes, we screened Janssen Jumpstarter library against P. falciparum asexual parasite and identified 7-N-substituted-3-oxadiazole quinolone hit class. We established structure–activity relationship optimized potency. analog WJM228 (17) showed robust metabolic stability in vitro, although aqueous solubility was limited. Forward genetic studies uncovered that...
There is an urgent need to populate the antimalarial clinical portfolio with new candidates because of resistance against frontline antimalarials. To discover chemotypes, we performed a high-throughput screen Janssen Jumpstarter library Plasmodium falciparum asexual blood-stage parasite and identified 2,3-dihydroquinazolinone-3-carboxamide scaffold. We defined SAR found that 8-substitution on tricyclic ring system 3-substitution exocyclic arene produced analogues potent activity parasites...
Significance Here, we describe inhibitors of the Plasmodium proteasome, an enzymatic complex that malaria parasites rely on to degrade proteins. Starting from developed treat cancer, derivatives were designed and synthesized with aim increasing potency against proteasome decreasing activity human enzyme. Biochemical cellular assays identified compounds exhibit selectivity potency, both in vitro vivo, at different stages parasite’s lifecycle. Cryo-electron microscopy revealed bind a...
To discover new antimalarials, a screen of the Janssen Jumpstarter library against Plasmodium falciparum uncovered N-acetamide indole hit class. The structure-activity relationship this chemotype was defined and culminated in optimized frontrunner analog WJM664, which exhibited potent asexual stage activity high metabolic stability. Resistant selection whole-genome sequencing revealed mutations PfATP4, validated as target by showing that analogs reduced potency parasites with...
Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to identification of potent, metabolically stable compounds with improved in vivo oral efficacy P. berghei mouse model and additional activity against parasite liver gametocyte stages, making them potential candidates for preclinical development. Inhibition hemozoin formation possibly contributes mechanism action.
Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure–activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to identification potent pyrazolopyridines, which showed good efficacy pharmacokinetics profiles. The lead compounds also proved be very parasite liver gametocyte stages, makes them high interest.
Formation of gametes in the malaria parasite occurs midgut mosquito and is critical to onward transmission. Transformation male gametocyte into microgametes, called microgametogenesis, an explosive cellular event one fastest eukaryotic DNA replication events known. The transformation microgametocyte eight flagellated microgametes requires reorganisation cytoskeleton, 22.9 Mb genome, axoneme formation host erythrocyte egress, all which occur simultaneously <20 minutes. Whilst high-resolution...
Malaria remains one of the most deadly infectious diseases, causing hundreds thousands deaths each year, primarily in young children and pregnant mothers. Here, we report discovery derivatization a series pyrazolo[3,4-b]pyridines targeting Plasmodium falciparum, deadliest species malaria parasite. Hit compounds this display sub-micromolar vitro activity against intraerythrocytic stage parasite as well little to no toxicity human fibroblast BJ liver HepG2 cell lines. In addition, our hit show...
Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of set PRS ATP-site binders, initially designed for human indications, led to identification 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing novel scaffold. Evidence designates cytoplasmic as the drug The frontrunner 1 and its active enantiomer 1-S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains development liver schizonts. No...
Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these not extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation gametocytocidal activity compounds from chemotypes identify novel starting...
Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified novel tetrazole-based series that shows fast-kill kinetics relatively low propensity develop high-level Preliminary structure-activity relationships were established including identification of subseries related amides with antiplasmodial activity. Assaying parasites resistance antimalarials led us test whether the had similar mechanism action...
Current malaria treatments are threatened by drug resistance, and new drugs urgently needed. In a phenotypic screen for antimalarials, we identified (S)-SW228703 ((S)-SW703), tyrosine amide with asexual blood liver stage activity fast-killing profile. Resistance to (S)-SW703 is associated mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) P. acetyl CoA transporter (PfACT), similarly several other compounds that share features such as fast liver-stage activity....
Structure–activity relationship studies involving N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles (PBI) identified several compounds possessing potent in vitro activities against the asexual blood, liver, and gametocyte stages of Plasmodium parasite with no cross-resistance to chloroquine. Frontrunner lead good absorption, distribution, metabolism, excretion (ADME) profiles were subjected vivo proof-of-concept NMRI mice harboring rodent P. berghei infection. This led identification 10...
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 Formation of gametes in the malaria parasite occurs midgut mosquito and is critical to onward transmission. Transformation male gametocyte into microgametes, called microgametogenesis, an explosive cellular event one fastest eukaryotic DNA replication events known. The transformation microgametocyte eight flagellated microgametes requires reorganisation cytoskeleton, 22.9 Mb genome, axoneme formation host erythrocyte egress, all which occur simultaneously <20 minutes. Whilst...
Abstract Current malaria treatments are threatened by drug resistance and new drugs urgently needed. In a phenotypic screen for antimalarials, we identified ( S )-SW228703 (( )-SW703), tyrosine amide with asexual blood liver stage activity fast-killing profile. Resistance to )-SW703 is associated mutations in Plasmodium falciparum cyclic amine locus Pf CARL) P. acetyl CoA transporter ACT), similarly several other compounds that share features such as fast liver-stage activity. Compounds...