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Professor Stephen Ward

Walter Myers Chair in Parasitology; Deputy Director LSTM

Areas of interest

Drug discovery, drug development and tropical pharmacology. Understanding the chemical, molecular and cellular basis of drug action and drug resistance in tropical pathogens with an emphasis on human malaria, TB and more recently the Neglected Tropical Diseases (NTDs). This fundamental information is then employed in the rational design and evaluation of novel chemotherapeutic agents and in improving the effectiveness of existing chemotherapeutic agents. Linked to this interest there is a focus on understanding fundamental pathogen-specific biological processes with a view to identifying unique targets for chemotherapy.

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 and was appointed as deputy Director of the School in 2001.

Research

The research focus has been towards understanding the mechanisms of action and resistance to anti infective drugs and the translation of basic science knowledge into new drugs for malaria, TB and more recently NTDs. Over the past 20 years the Drug Discovery Unit in Liverpool has developed a molecule to man initiative aimed at translating basic scientific knowledge into products. This has resulted in the international registration of two drugs, the progression of a further four molecules into human clinical trials and progression of six molecules into formal pre-clinical evaluation.

Malaria

Artemisinin mechanism of action and resistance remains a research focus. Using filed isolates from S.E. Asia displaying the reduced in vivo clearance phenotype alongside laboratory selected lines we are applying a range of molecular and biochemical approaches to characterise these parasites. Linked to these studies is a medicinal chemistry programme that has a) generated novel probe peroxides that are being used as chemical biology tools to identify drug targets within the malaria parasite and b) delivered a new candidate antimalarial drug for development with the potential of delivering a single dose cure. The group is adopting a systems pharmacology approach to understanding drug action and has established a range of technology platforms that are generating multi-parameter data sets for all current and investigational antimalarial molecules in the public domain. The project is configured to provide novel insights into important aspects of parasite biology as well as contributing towards our drug discovery programmes. The group also has active research programmes focussed on energy metabolism in malaria parasites, the folate pathway and the functional characterisation of parasite transporters. In each case research is focussed in understanding the underlying biochemistry and cell biology but with the view of exploiting this information through our drug discovery activities. 

TB

The group, in collaboration with Dr Biagini, is focussed on defining redox systems and energy metabolism in replicating and non-replicating TB. This work has generated a full drug discovery programme, currently at lead optimisation, targeting a novel enzyme target that is essential in all parasite cell cycle states.  Linked with the malaria programme a systems pharmacology approach is also being used to define mechanisms of action of current and investigational anti-TB molecules.

NTDs

As part of the AWOL initiative, co-ordinated by Professor M Taylor, we have generated a series of drug-like hit molecules through an extensive library screening exercise. The search for additional leads is on going with over 2million compounds having been screened to date.. Hits have been triaged and prioritised and are in the process of lead optimisation involving iterative rounds of medicinal chemistry and testing in the in vitro and in vivo nematode screens and counter screens. The research delivered two new candidate molecules for onward development. Supporting the better deployment of existing AWOL treatment strategies the group is also adopting a detailed PK/PD approach to evaluating the best monotherapy and combination therapy options currently available for immediate use.

Recent publications: 

    Selected publications

    • Selected Publications

      Salcedo-Sora JE, Ochong E, Beveridge S, Johnson D, Nzila A, Biagini GA, Stocks PA, O'Neill PM, Krishna S, Bray PG, Ward SA. (2011) The Molecular Basis of Folate Salvage in Plasmodium falciparum: Characterization of two folate transporters. J Biol Chem. 2011 Dec 30;286(52):44659-68. Epub 2011 Oct 13.

      Biagini GA, Fisher N, Shone AE, Mubaraki MA, Srivastava A, Hill A, Antoine T, Warman AJ, Davies J, Pidathala C, Amewu RK, Leung SC, Sharma R, Gibbons P, Hong DW, Pacorel B, Lawrenson AS, Charoensutthivarakul S, Taylor L, Berger O, Mbekeani A, Stocks PA, Nixon GL, Chadwick J, Hemingway J, Delves MJ, Sinden RE, Zeeman AM, Kocken CH, Berry NG, O'Neill PM, Ward SA. (2012) Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria. Proc Natl Acad Sci U S A. 2012 May 22;109(21):8298-303. Epub 2012 May 7.

      Fisher N, Abd Majid R, Antoine T, Al-Helal M, Warman AJ, Johnson DJ, Lawrenson AS, Ranson H, O'Neill PM, Ward SA, Biagini GA. (2012) Cytochrome b mutation Y268S conferring atovaquone resistance phenotype in malaria parasite results in reduced parasite bc1 catalytic turnover and protein expression. J Biol Chem. 2012 Mar 23;287(13):9731-41. Epub 2012 Jan 26.

      Patzewitz EM, Salcedo-Sora JE, Wong EH, Sethia S, Stocks PA, Maughan SC, Murray JA, Krishna S, Bray PG, Ward SA, Müller S. (2012) Glutathione Transport: A New Role for PfCRT in Chloroquine Resistance. Antioxid Redox Signal. 2012 Dec 20.

      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 ofPlasmodium falciparum and Mycobacterium tuberculosis kinetic and high-throughput assays. Methods in Enzymology456: 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 andWard 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 andWard 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 Letters18: 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 Cell15: 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.