Irene Hallyburton
University of Dundee
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Publication
Featured researches published by Irene Hallyburton.
Nature | 2010
Julie A. Frearson; Stephen Brand; Stuart P. McElroy; Laura A. T. Cleghorn; Ondrej Smid; Laste Stojanovski; Helen P. Price; M. Lucia S. Güther; Leah S. Torrie; David A. Robinson; Irene Hallyburton; Chidochangu P. Mpamhanga; James A. Brannigan; Anthony J. Wilkinson; Michael R. Hodgkinson; Raymond Hui; Wei Qiu; Olawale G. Raimi; Daan M. F. van Aalten; Ruth Brenk; Ian H. Gilbert; Kevin D. Read; Alan H. Fairlamb; Michael A. J. Ferguson; Deborah F. Smith; Paul G. Wyatt
African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for ∼30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target—T. brucei N-myristoyltransferase—leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.
Nature | 2015
Beatriz Baragaña; Irene Hallyburton; Marcus C. S. Lee; Neil R. Norcross; Raffaella Grimaldi; Thomas D. Otto; William R. Proto; Andrew M. Blagborough; Stephan Meister; Grennady Wirjanata; Andrea Ruecker; Leanna M. Upton; Tara S. Abraham; Mariana Justino de Almeida; Anupam Pradhan; Achim Porzelle; María Santos Martínez; Judith M. Bolscher; Andrew Woodland; Suzanne Norval; Fabio Zuccotto; John Thomas; Frederick R. C. Simeons; Laste Stojanovski; Maria Osuna-Cabello; Patrick M. Brock; Thomas S. Churcher; Katarzyna A. Sala; Sara E. Zakutansky; María Belén Jiménez-Díaz
There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
Journal of Medicinal Chemistry | 2012
Stephen Brand; Laura A. T. Cleghorn; Stuart P. McElroy; David A. Robinson; Victoria Smith; Irene Hallyburton; Justin R. Harrison; Neil R. Norcross; Daniel Spinks; Tracy Bayliss; Suzanne Norval; Laste Stojanovski; Leah S. Torrie; Julie A. Frearson; Ruth Brenk; Alan H. Fairlamb; Michael A. J. Ferguson; Kevin D. Read; Paul G. Wyatt; Ian H. Gilbert
N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.
Antimicrobial Agents and Chemotherapy | 2013
Manu De Rycker; Irene Hallyburton; John Thomas; Lorna Campbell; Susan Wyllie; Dhananjay Joshi; Scott Cameron; Ian H. Gilbert; Paul G. Wyatt; Julie A. Frearson; Alan H. Fairlamb; David W. Gray
ABSTRACT Visceral leishmaniasis is a neglected tropical disease with significant health impact. The current treatments are poor, and there is an urgent need to develop new drugs. Primary screening assays used for drug discovery campaigns have typically used free-living forms of the Leishmania parasite to allow for high-throughput screening. Such screens do not necessarily reflect the physiological situation, as the disease-causing stage of the parasite resides inside human host cells. Assessing the drug sensitivity of intracellular parasites on scale has recently become feasible with the advent of high-content screening methods. We describe here a 384-well microscopy-based intramacrophage Leishmania donovani assay and compare it to an axenic amastigote system. A panel of eight reference compounds was tested in both systems, as well as a human counterscreen cell line, and our findings show that for most clinically used compounds both axenic and intramacrophage assays report very similar results. A set of 15,659 diverse compounds was also screened using both systems. This resulted in the identification of seven new antileishmanial compounds and revealed a high false-positive rate for the axenic assay. We conclude that the intramacrophage assay is more suited as a primary hit-discovery platform than the current form of axenic assay, and we discuss how modifications to the axenic assay may render it more suitable for hit-discovery.
Biochemical Pharmacology | 2010
Deuan C. Jones; Irene Hallyburton; Laste Stojanovski; Kevin D. Read; Julie A. Frearson; Alan H. Fairlamb
Graphical abstract Phenotypic screening of the LOPAC library identified several potent and selective inhibitors of African trypanosomes. The κ-opioid agonist (+)-U50,488 represents a novel lead for drug discovery against sleeping sickness.
PLOS Neglected Tropical Diseases | 2012
Ross A. Paveley; Nuha R. Mansour; Irene Hallyburton; Leo S. Bleicher; Alex E. Benn; Ivana Mikic; Alessandra Guidi; Ian H. Gilbert; Andrew L. Hopkins; Q. D. Bickle
Sole reliance on one drug, Praziquantel, for treatment and control of schistosomiasis raises concerns about development of widespread resistance, prompting renewed interest in the discovery of new anthelmintics. To discover new leads we designed an automated label-free, high content-based, high throughput screen (HTS) to assess drug-induced effects on in vitro cultured larvae (schistosomula) using bright-field imaging. Automatic image analysis and Bayesian prediction models define morphological damage, hit/non-hit prediction and larval phenotype characterization. Motility was also assessed from time-lapse images. In screening a 10,041 compound library the HTS correctly detected 99.8% of the hits scored visually. A proportion of these larval hits were also active in an adult worm ex-vivo screen and are the subject of ongoing studies. The method allows, for the first time, screening of large compound collections against schistosomes and the methods are adaptable to other whole organism and cell-based screening by morphology and motility phenotyping.
RSC Advances | 2013
Mostafa E. Rateb; Irene Hallyburton; Wael E. Houssen; Alan T. Bull; Michael Goodfellow; Rakesh Santhanam; Marcel Jaspars; Rainer Ebel
An established culture of Aspergillus fumigatus MBC-F1-10 proved to be very receptive to external stimuli and reacted with the production of secondary metabolites which were undetectable when the fungus was grown under standard conditions. Firstly, co-cultivation with the type strain of Streptomyces bullii, an isolate from hyper-arid Atacama desert soil, led to the isolation of ergosterol 1, seven metabolites belonging to the diketopiperazine alkaloids; brevianamide F 2, spirotryprostatin A 3, 6-methoxy spirotryprostatin B 4, fumitremorgin C and its 12,13-dihydroxy derivative (5–6), fumitremorgin B 7, and verruculogen 8, in addition to 11-O-methylpseurotin A 9 and its new isomer 11-O-methylpseurotin A210. In an independent experiment, addition of N-butyryl-DL-homoserine lactone to the culture medium led to the production of emestrins A and B (11–12). Neither microbe produced these compounds when cultured alone. The structures of all compounds were elucidated using NMR spectroscopic techniques and mass spectrometric analysis. The isolated compounds were tested for their potential antibacterial and antiprotozoal activities.
FEBS Letters | 2007
Ian R. Kelsall; Shonagh Munro; Irene Hallyburton; Judith L. Treadway; Patricia T.W. Cohen
The inhibition of hepatic glycogen‐associated protein phosphatase‐1 (PP1‐GL) by glycogen phosphorylase a prevents the dephosphorylation and activation of glycogen synthase, suppressing glycogen synthesis when glycogenolysis is activated. Here, we show that a peptide (280LGPYY284) comprising the last five amino acids of GL retains high‐affinity interaction with phosphorylase a and that the two tyrosines play crucial roles. Tyr284 deletion abolishes binding of phosphorylase a to GL and replacement by phenylalanine is insufficient to restore high‐affinity binding. We show that a phosphorylase inhibitor blocks the interaction of phosphorylase a with the GL C‐terminus, suggesting that the latter interaction could be targeted to develop an anti‐diabetic drug.
Journal of Medicinal Chemistry | 2014
Stephen Brand; Neil R. Norcross; Stephen Thompson; Justin R. Harrison; Victoria Smith; David A. Robinson; Leah S. Torrie; Stuart P. McElroy; Irene Hallyburton; Suzanne Norval; Paul Scullion; Laste Stojanovski; Frederick R. C. Simeons; Daan M. F. van Aalten; Julie A. Frearson; Ruth Brenk; Alan H. Fairlamb; Michael A. J. Ferguson; Paul G. Wyatt; Ian H. Gilbert; Kevin D. Read
Trypanosoma bruceiN-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood–brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.
Journal of Medicinal Chemistry | 2015
Laura A. T. Cleghorn; Sébastien Albrecht; Laste Stojanovski; Frederick R. J. Simeons; Suzanne Norval; Robert Kime; Iain T. Collie; Manu De Rycker; Lorna Campbell; Irene Hallyburton; Julie A. Frearson; Paul G. Wyatt; Kevin D. Read; Ian H. Gilbert
There is an urgent need for new, brain penetrant small molecules that target the central nervous system second stage of human African trypanosomiasis (HAT). We report that a series of novel indoline-2-carboxamides have been identified as inhibitors of Trypanosoma brucei from screening of a focused protease library against Trypanosoma brucei brucei in culture. We describe the optimization and characterization of this series. Potent antiproliferative activity was observed. The series demonstrated excellent pharmacokinetic properties, full cures in a stage 1 mouse model of HAT, and a partial cure in a stage 2 mouse model of HAT. Lack of tolerability prevented delivery of a fully curative regimen in the stage 2 mouse model and thus further progress of this series.