A5079503397- RNA and protein synthesis mechanisms
- HIV/AIDS drug development and treatment
- Malaria Research and Control
- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Asymmetric Synthesis and Catalysis
- Pneumocystis jirovecii pneumonia detection and treatment
- Biochemical and Molecular Research
- Fluorine in Organic Chemistry
- Parasitic Infections and Diagnostics
- RNA modifications and cancer
- Synthetic Organic Chemistry Methods
- Synthesis and Biological Evaluation
- Tuberculosis Research and Epidemiology
- Carbohydrate Chemistry and Synthesis
- Mosquito-borne diseases and control
- Click Chemistry and Applications
- vaccines and immunoinformatics approaches
- DNA Repair Mechanisms
- Synthesis of β-Lactam Compounds
- Asymmetric Hydrogenation and Catalysis
- Parasites and Host Interactions
- Synthesis and Catalytic Reactions
- Hepatitis C virus research
- Microbial Natural Products and Biosynthesis
Wellcome Centre for Anti-Infectives Research
2018-2025
University of Dundee
2016-2025
Drug Discovery Laboratory (Norway)
2025
Trinity College Dublin
2002-2004
University of Strathclyde
2002
University of Edinburgh
2002
Universidad de Oviedo
1994-2000
Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment malaria in particular, are high priority; however, there few chemically validated targets. The natural product cladosporin is active against blood- liver-stage Plasmodium falciparum Cryptosporidium parvum cell-culture studies. Target deconvolution P. has shown that inhibits lysyl-tRNA synthetase ( Pf KRS1). Here, we report identification a series...
There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential targets are being validated Plasmodium species. Given the high attrition rate and cost of discovery, it important to select most likely deliver progressible candidates. In this paper, we describe criteria that consider for selecting discovery. We analysis number Malaria Drug Accelerator (MalDA) pipeline, which has allowed us prioritize ready enter process. This...
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...
Identification of novel drug targets is a key component modern discovery. While antimalarial are often identified through the mechanism action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space also constrained by existing compound libraries phenotypic assay conditions. Leveraging recent advances in protein structure prediction, we systematically assessed Plasmodium falciparum genome 867 candidate with evidence...
The antiplasmodial activity, DMPK properties, and efficacy of a series quinoline-4-carboxamides are described. This was identified from phenotypic screen against the blood stage Plasmodium falciparum (3D7) displayed moderate potency but with suboptimal physicochemical properties poor microsomal stability. screening hit (1, EC50 = 120 nM) optimized to lead molecules low nanomolar in vitro potency. Improvement pharmacokinetic profile led several compounds showing excellent oral P. berghei...
The direct enzymatic synthesis of peptides from amino acids is widely used as a useful alternative to chemical synthesis. However, good yields such enzyme-catalyzed reactions require altered reaction conditions overcome the bias for hydrolysis in aqueous medium. We argue that synthesis/hydrolysis equilibrium can be shifted toward medium by immobilizing amine on solid support. In this report, we show first examples solid-phase peptide catalyzed protease bulk buffer.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHigh Diastereoselective Synthesis of Threo or Erythro Aminoalkyl Epoxides from .alpha.-Amino AcidsJose Barluenga, Beatriz Baragana, and Jose M. ConcellonCite this: J. Org. Chem. 1995, 60, 21, 6696–6699Publication Date (Print):October 1, 1995Publication History Published online1 May 2002Published inissue 1 October 1995https://pubs.acs.org/doi/10.1021/jo00126a019https://doi.org/10.1021/jo00126a019research-articleACS PublicationsRequest reuse...
Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify that selectively inhibit PfProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures solved apo, as well substrate- and inhibitor-bound forms PfProRS. We identified two new bind outside active site. These...
Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy this at-risk patient population. Additional safe therapeutics are urgently required to tackle unmet medical need. However, the development anti-cryptosporidial drugs hindered lack understanding optimal compound properties treat gastrointestinal infection. To address...
Abstract Nucleophilic amino acids are important in covalent drug development yet underutilized as anti-microbial targets. Chemoproteomic technologies have been developed to mine chemically accessible residues via their intrinsic reactivity towards electrophilic probes but cannot discern which reactive sites contribute protein function and should therefore be prioritized for discovery. To address this, we a CRISPR-based oligo recombineering (CORe) platform support the rapid identification,...
There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe toolkit support therapeutic exploitation promising target, lysyl tRNA synthetase (PfKRS). The includes resistant mutants probe resistance mechanisms on-target engagement specific chemotypes; hybrid KRS protein...
Abstract Tuberculosis is a major global cause of both mortality and financial burden mainly in low middle-income countries. Given the significant ongoing rise drug-resistant strains Mycobacterium tuberculosis within clinical setting, there an urgent need for development new, safe effective treatments. Here drug-like series based on fused dihydropyrrolidino-pyrimidine scaffold described. The has been developed against M. lysyl-tRNA synthetase (LysRS) cellular studies support this mechanism...
Introduction Cryptosporidiosis is a leading cause of diarrheal-associated morbidity and mortality, predominantly affecting children under 5 years old in low-and-middle-income countries. There no effective treatment vaccine. New therapeutics are emerging from drug discovery efforts. It critical that mode action studies performed alongside to ensure the best clinical outcomes. Unfortunately, technology identify validate targets for Cryptosporidium severely lacking. Methods We used C. parvum...
Artemisinin-based combination therapies have been crucial in driving down the global burden of malaria, world's largest parasitic killer. However, their efficacy is now threatened by emergence resistance Southeast Asia and sub-Saharan Africa. Thus, there a pressing need to develop new antimalarials with diverse mechanisms action. One area Plasmodium metabolism that has recently proven rich exploitable antimalarial targets protein synthesis, compound targeting elongation factor 2 clinical...
There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality TB and combat resistance current treatments. Through both chemical genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential mycobacterial survival attractive target Mycobacterium growth inhibitors. A benzofuran series inhibitors that targeted Pks13 thioesterase domain, failed progress preclinical development due concerns over cardiotoxicity....
The cationic steroidal receptors 9 and 11 have been synthesized from cholic acid 3. Receptor extracts N-acetyl-α-amino acids aqueous media into chloroform with enantioselectivities (L:D) of 7–10:1. lipophilic variant has employed for the enantioselective transport N-acetylphenylalanine, a) through dichloromethane (DCM) dichloroethane (DCE) bulk liquid membranes (U-tube apparatus), b) 2.5 % (v/v) octanol/hexane via hollow fibre membrane contactors. Significant multiple turnovers were observed...
Cholic acid 2a has been converted into two new orthogonally-protected triamino scaffolds, 13 and 14. The synthesis proceeds via the bis-Boc-NH-substituted azide 10, for which an improved preparation is described. After removal of Boc groups, axial amines are differentiated through a novel monoprotection employing 1-(2-nitrobenzenesulfonyloxy)-benzotriazole 29. Regioselectivity ≥50 : 1 achieved, presumably reflecting exceptional sensitivity to steric hindrance. Protection remaining amino...
ABSTRACT There is currently a public health crisis due to the rise of multi-drug-resistant tuberculosis cases, as well in number deaths from tuberculosis. To achieve United Nations Sustainable Development Goal ending epidemic by 2030, new treatments are urgently required. We previously reported discovery 49 , pre-clinical candidate that acted through inhibition Mycobacterium lysyl-tRNA synthetase (LysRS). In this report, full medicinal chemistry program reviewed original hit optimised lead....
Almost enantiomerically pure halogenated α-hydroxy and α-amino ketones can be prepared from O-protected lactates tribenzylated alanine, respectively; whilst amino 3g have also been transformed into the epoxide 7 with high diastereoselectivity.