Liverpool School of Tropical Medicine
Background
Stephen Ward graduated in Pharmacology and Physiology from Aston University in 1979 and obtained his PhD in Biochemical Pharmacology from Liverpool University in 1984. He spent the next two years as a Senior Research Fellow at Vanderbilt University in Tennessee USA before returning to the Liverpool School of Tropical Medicine as the Wolfson Lecturer in Tropical Pharmacology. In 1990 he moved to a lectureship in Pharmacology in the University of Liverpool and was awarded a chair in Pharmacology in 1999. He returned to the Liverpool School of Tropical Medicine in 2000 as Walter Myers Professor and Head of Molecular and Biochemical Parasitology.
Research
The research focus has been towards understanding the mechanisms of action and resistance to antimalarial drugs and the translation of basic science knowledge into new drugs for malaria. Key achievements include a large body of work that has established that drug access to hematin controls parasite susceptibility to the antimalarial chloroquine. Furthermore using a combination of transfection technology and drug selection I have demonstrated that a single mutation in the chloroquine resistance gene pfCRT is capable of controlling resistance. Away from the 4-aminoquinolines and in collaboration with colleagues at St Georges, we have been able to demonstrate a role for pfATPase6 as a target for artemisinin action.
Over the past decade I have contributed towards the development of a molecule to man initiative in Liverpool aimed at translating basic scientific knowledge into products. I have been involved in all stages of the development and registration of the antimalarial Lapdap in partnership with GSK, DFID and WHO-TDR, with a principle role in the preclinical pharmacology and human disposition studies as well as being a member of the product development team (PDT). I have an equivalent role in two further PDT’s funded by MMV and GSK, one involved
in the development of an artemisinin combination (CDA) that is about to enter phase III clinical trials and a second (the isoquine project) at candidate selection. Isoquine is a novel molecule designed in Liverpool based on our understanding of the relationship between chemical structure, drug action and drug toxicity obtained from our basic research programmes funded in part by the Wellcome Trust.
Current grants
Wellcome Trust £873,943 (2008-2011) "Population pharmacokinetic-pharmacopdynamic modelling to optimise treatments for HIV, TB and malaria". Co-applicant with Drs Khoo and Prof Back
Gates Foundation $3,300,000 (2008-2011) "lomgitudinal studies as part of the ACT consortium". Co-applicant on the LSTM sub-contract
Gates Foundation $96,000 (2008-2009) "Antimalrial drug pharmacokinetics for the Malaria in Pregnancy Consortia". PI
Wellcome Trust £1,400,000 (2008-2010) "Seeding Drug Discovery - pfNDH2 as a novel antimalarial drug". PI
European Commision €500,000 (2008-2009) "CRIMALDDI". PI
Wellcome Trust £39,962 (2007-2009) "“Molecular basis of artemisinin resistance in P. falciparum". PI with Prof AG Craig
Gates Foundation $850,000 (2007-2012) "Development Pharmacology of novel AWOL treatments". PI
IVCC $2,036,186 (2007-2009) "Novel pyrethroid resistance breakers". PI with Professor P O’Neill
European Commission €1,948880 (2007-2010) "The safety pharmacology of artemisinins when used to reverse pathophysiology of malaria in pregnancy". PI
BRC £331,710 (2007-2012) "TB diagnostics" (01CE0). PI
Gates Foundation £601,340 (2007-2012) "AWOL drug discovery programme". PI
Wellcome Trust £281,658 (2007–2010) "LOTLink" (082112/Z/07/Z). PI with Profs Winstanley, Back and Dr Khoo
European Commission €17,500,000 (2006-2011) "Antimal an integrated project for new antimalarial drugs". PI
Leverhulme £140,521 (2006-2009) "A new drug target against malaria". With Dr G Biagini
Selected recent publications
O'Neill PM, Amewu RK, Nixon GL, ElGarah FB, Mungthin M, Chadwick J, Shone AE, Vivas L, Lander H, Barton V, Muangnoicharoen S, Bray PG, Davies J, Park BK, Wittlin S, Brun R, Preschel M, Zhang K and Ward SA (2010). Identification of a 1,2,4,5-tetraoxane antimalarial drug-development candidate (RKA 182) with superior properties to the semisynthetic artemisinins. Angewandte Chemie International Edition 49: 5693-5697.
Lucumi E, Darling C, Jo H, Napper AD, Chandramohandas R, Fisher N, Shone AE, Jing H, Ward SA, Biagini GA, Degrado WF, Diamond SL and Greenbaum DC (2010). Discovery of potent small molecule inhibitors of multi-drug resistant P. falciparum using a novel miniaturized high-throughput luciferase-based assay. Antimicrobial Agents and Chemotherapy 54: 3597-3604.
Barton V, Fisher N, Biagini GA, Ward SA and O'Neill PM (2010). Inhibiting Plasmodium cytochrome bc(1): a complex issue. Current Opinion in Chemical Biology 14: 440-446.
Barton V, Ward SA, Chadwick J, Hill A and O'Neill PM (2010). Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics. Journal of Medicinal Chemistry 53: 4555-4559.
de Souza JB, Okomo U, Alexander ND, Aziz N, Owens BM, Kaur H, Jasseh M, Muangnoicharoen S, Sumariwalla PF, Warhurst DC, Ward SA, Conway DJ, Ulloa L, Tracey KJ, Foxwell BM, Kaye PM and Walther M (2010). Oral activated charcoal prevents experimental cerebral malaria in mice and in a randomized controlled clinical trial in man did not interfere with the pharmacokinetics of parenteral artesunate. PLOS One 5: e9867.
Amewu R, Gibbons P, Mukhtar A, Stachulski AV, Ward SA, Hall C, Rimmer K, Davies J, Vivas L, Bacsa J, Mercer AE, Nixon G, Stocks PA and O'Neill PM (2010). Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols. Organic and Biomolecular Chemistry 8: 2068-2077.
O'Neill PM, Barton VE and Ward SA (2010). The molecular mechanism of action of artemisinin - the debate continues. Molecules 15: 1705-1721.
Chadwick J, Jones M, Mercer AE, Stocks PA, Ward SA, Park BK and O'Neill PM (2010). Design, synthesis and antimalarial/ anticancer evaluation of spermidine linked artemisinin conjugates designed to exploit polyamine transporters in Plasmodium falciparum and HL-60 cancer cell lines. Bioorganic and Medicinal Chemistry 18: 2586-2597.
Fisher N, Warman AJ, Ward SA and Biagini GA (2009). Chapter 17 Type II NADH: quinone oxidoreductases of Plasmodium falciparum and Mycobacterium tuberculosis kinetic and high-throughput assays. Methods in Enzymology 456: 303-320.
Lian LY, Al-Helal M, Roslaini AM, Fisher N, Bray PG, Ward SA and Biagini GA (2009). Glycerol: an unexpected major metabolite of energy metabolism by the human malaria parasite. Malaria Journal 8: 38.
O'Neill PM, Shone AE, Stanford D, Nixon G, Asadollahy E, Park BK, Maggs JL, Roberts P, Stocks PA, Biagini G, Bray PG, Davies J, Berry N, Hall C, Rimmer K, Winstanley PA, Hindley S, Bambal RB, Davis CB, Bates M, Gresham SL, Brigandi RA, Gomez-de-Las-Heras FM, Gargallo DV, Parapini S, Vivas L, Lander H, Taramelli D and Ward SA (2009). Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4'-fluoro and 4'-chloro analogues of amodiaquine. Identification of a suitable "back-up" compound for N-tert-butyl isoquine. Journal of Medicinal Chemistry 52: 1828-1844.
O'Neill PM, Park BK, Shone AE, Maggs JL, Roberts P, Stocks PA, Biagini GA, Bray PG, Gibbons P, Berry N, Winstanley PA, Mukhtar A, Bonar-Law R, Hindley S, Bambal RB, Davis CB, Bates M, Hart TK, Gresham SL, Lawrence RM, Brigandi RA, Gomez-Delas-Heras FM, Gargallo DV and Ward SA (2009). Candidate selection and preclinical evaluation of N-tert-Butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century. Journal of Medicinal Chemistry 52: 1408–1415.
Johnson DJ, Owen A, Plant N, Bray PG and Ward SA (2008). Drug-regulated expression of Plasmodium falciparum P-glycoprotein homologue 1: a putative role for nuclear receptors. Antimicrobial Agents and Chemotherapy 52:1438-1445.
Biagini GA, Fisher N, Berry N, Stocks PA, Meunier B, Williams DP, Bonar-Law R, Bray PG, Owen A, O'Neill PM and Ward SA (2008). Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex. Molecular Pharmacology 73: 1347-1355.
Bell DJ, Nyirongo SK, Mukaka M, Zijlstra EE, Plowe CV, Molyneux ME and Ward SA, Winstanley PA (2008). Sulfadoxine-pyrimethamine-based combinations for malaria: a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi. PLosS One 3: e1578.
Ellis GL, Amewu R, Hall C, Rimmer K, Ward SA and O'Neill PM (2008). An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity. Bioorganic and Medicinal Chemistry Letters 18: 1720-1724.
Stocks PA, Bray PG, Barton VE, Al-Helal M, Jones M, Arouja NC, Gibbons P, Ward SA, Hughes RA, Biagini GA, Davies J, Amewu R, Mercer AE, Ellis G and O’Neill PM (2007). Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisynthetic and synthetic endoperoxide antimalarial drugs. Angewandte Chemie (International Ed in English) 46: 6278-6283.
Ward SA, Sevene E, Hastings IM, Nosten F and McGready R (2007). Antimalarial drugs and pregnancy: safety, pharmacokinetics and pharmacovigilence. Lancet Infectious Diseases 7: 136-144.
Bray PG, Mungthin M, Hastings IM, Biagini GA, Saidu DA, Lakshmanan V, Johnson DJ, Hughes RH, Stocks PL, O’Neill PM, Fidock DA, Warhurst DC and Ward SA (2006). PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX. Molecular Microbiology 62: 238-251.
Lakshmanan V, Bray PG, Verdier-Pinard D, Johnson DJ, Horrocks P, Alakpa GE, Muhle RA, Hughes RH, Ward SA, Krogstad DJ, Sidhu AB and Fidock DA (2005). A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO Journal 24: 2294-2305.
Biagini GA, Pasini EM, Hughes R, De Koning HP, Vial HJ, O’Neill PM, Ward SA and Bray PG (2004). Characterisation of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial drugs. Blood 104: 3372-3377.
O’ Neill PM, Stocks PA, Pugh MD Araujo NC, Korshin EE, Bickley JF, Ward SA, Bray PG, Pasini E, Davies J, Verissimo E and Bachi MD (2004). Design and synthesis of endoperoxide antimalarial pro-drug models: prototypes for selective intraparasitic generation of cysteine protease inhibitors and other parasitocidal species: Angewandte Chemie (International Ed in English) 43: 4193-4197.
Johnson DJ, Fidock DA, Mungthin M, Lakshmanan V, Sidhu ABS, Bray PG and Ward SA (2004). Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Molecular Cell 15: 867-877.
Eckstein-Ludwig U, Webb RJ, van Goethem IDA, East JM, Lee AG, Kimura M, O’Neill PM, Bray PG, Ward SA and Krishna S (2003). Artemisinins target the SERCA of Plasmodium falciparum. Nature 424: 957-961.