Research Activities – Associate Professor Angus Bell
Angus Bell, BSc (Edin.) MA (Dubl.) PhD (Brit. Col.) FTCD – Associate Professor.
Malaria Research Group
Malaria continues to take a huge toll of human life, economic development and social cohesion in much of the world. It is caused by protozoa of the genus Plasmodium that are spread by mosquito vectors and multiply in the hepatocytes and erythrocytes of infected humans. The spread of drug-resistant parasites, particularly those of the most lethal species, P. falciparum , is making control (and attempted eradication) of malaria more difficult. The Malaria Research Group at Trinity College is dedicated to investigating aspects of the biochemistry and molecular cell biology of blood-stage P. falciparum, the biochemical pharmacology of antimalarial agents and development of novel antimalarial drugs.
(i) Identification of new antimalarial drug leads and/or targets. We have identified the major parasite receptors for the immunosuppressive drugs cyclosporin A and FK506. Non-immunosuppressive derivatives of these drugs have potent antimalarial activity and we are exploring them as antimalarial leads. We are also characterizing the functional properties and biological roles of these receptors (immunophilins) and their potential as drug targets. Another potential target is tubulin, the major constituent of microtubules that are essential for development of the parasite inside its host erythrocyte. We have developed ligand-binding assays for P. falciparum tubulins and are exploring the potential of herbicide derivatives as parasite-selective microtubule inhibitors.
(ii) Development of antimalarial drugs less prone to resistance. One approach to developing ‘resistance-proof' drugs may be to target pathogenic processes rather the parasite viability. We are exploring the mechanisms by which P. falciparum interferes with host erythropoiesis and the potential of this as a target for ‘anti-disease' therapy of severe malarial anaemia.
(iii) New approaches to antimalarial chemotherapy. Combination therapy is favoured for malaria and discovery of new synergistic combinations could enhance the efficacy of antimalarial therapy. Interaction data can also give clues about the mechanisms of action of new antimalarial compounds. We are systematically investigating interactions among antimalarial drugs and between these drugs and novel antimalarial compounds discovered in high-throughput screens.
Dr. Kathy Andrews, Esketis Institute of Griffith University & Queensland Institute of Medical Research, Brisbane, Australia.
Dr. James Barlow, Royal College of Surgeons in Ireland, Dublin.
Dr. Giancarlo Biagini, Liverpool School of Tropical Medicine, UK.
Prof. Paul Engel, University College Dublin.
Prof. John Hinde, National University of Ireland Galway.
Prof. David G. Lloyd, Dr. Darren Fayne, School of Biochemistry & Immunology, TCD.
Dr. Miguel Prudêncio, Instituto de Medicina Molecular, Lisbon, Portugal.
Prof. Denis Shields, Drs. Anthony Chubb, Catherine Mooney, University College Dublin.
Prof. John J. Walsh, School of Pharmacy & Pharmaceutical Sciences, TCD.
Dr. D. Boehm firstname.lastname@example.org
Malaria Research Group Publications
Dempsey E, Prudêncio M, Fennell BJ, Gomes-Santos CS, Barlow JW & Bell A. Antimitotic herbicides bind to an unidentifed site on malarial parasite tubulin and block development of liver-stage Plasmodium parasites. Mol. Biochem. Parasitol. In press. DOI: http://dx.doi.org/10.1016/j.molbiopara.2013.03.001
Mara C, Dempsey E, Bell A & Barlow JW. Synthesis and evaluation of phenoxyoxazaphospholidine, phenoxyoxazaphosphinane, and benzodioxaphosphininamine sulfides and related compounds as potential anti-malarial agents. Bioorg. Med. Chem. Lett., in press.
Bell A & Boehm D. Anti-disease therapy for malaria: ‘resistance proof'? Curr. Pharm. Des. 19: 300-306 (2013) [PMID: 22973884].
Bell A. Editorial: Antimalarial drug discovery and design in the era of resistance. Curr Pharm Des 19: 264-265 (2013) [PMID: 22973889].
Marín-Menéndez A, Monaghan P & Bell A. A family of cyclophilin-like molecular chaperones in Plasmodium falciparum. Mol. Biochem. Parasitol, 184: 44-47 (2012).
Mara C, Dempsey E, Bell A & Barlow JW. Synthesis and evaluation of phosphoramidate and phosphorothioamidate analogues of amiprophos methyl as potential antimalarial agents. Bioorg. Med. Chem. Lett. 21: 6180-6183 (2011).
Bell A. Antimalarial peptides: the long and the short of it. Curr. Pharm. Des. 17: 2719-2731 (2011).
Marín-Menéndez A & Bell A. Overexpression, purification and assessment of cyclosporin binding of a family of cyclophilins and cyclophilin-like proteins of the human malarial parasite Plasmodium falciparum. Protein Expr. Purif. 78: 225-234 (2011).
McKay PB, Peters MB, Carta G, Flood CT, Dempsey E, Bell A, Berry C, Lloyd DG & Fayne D. Identification of plasmepsin inhibitors as selective antimalarial agents using ligand based drug design. Bioorg. Med. Chem. Lett. 21: 3335-3341 (2011).
Dempsey E, Fennell BJ, Mara C, Barlow JW & Bell A. Antimitotic herbicides block development of intra-erythrocytic Plasmodium falciparum by binding to a novel site on tubulin. Ir J Med Sci 180: S293 (2011).
Marín-Menéndez A & Bell A. Identification and characterization of novel Plasmodium falciparum cyclophilins and their roles in the antimalarial actions of cyclosporin A and derivatives. Malaria J. 9 (supp 2): O3 (2010).
Naughton JA, Nasizadeh S, Bell A. Downstream effects of haemoglobinase inhibition in Plasmodium falciparum -infected erythrocytes. Mol. Biochem. Parasitol. 173: 81-87 (2010).
Aparicio I, Marín-Menéndez A, Bell A, Engel P. Susceptibility of Plasmodium falciparum to glutamate dehydrogenase inhibitors - a possible new antimalarial target. Mol. Biochem. Parasitol. 172: 152-155 (2010).
Walsh JJ & Bell A. Hybrid drugs for malaria. Curr. Pharm. Design 15: 2790-2785 (2009).
Kiboi DM, Irungu BN, Langat B, Wittlin S, Brun R, Chollet J, Abiodun O, Nganga JK, Nyambati VCS, Rukunga GM, Bell A & Nzila A. Plasmodium berghei ANKA: selection of resistance to piperaquine and lumefantrine in a mouse model. Exp. Parasitol. 122: 196-202 (2009).
Bell A. Letter to the Editor on effect of cyclosporine on parasitemia and survival of Plasmodium berghei-infected mice. Biochem. Biophys. Res. Commun. 378: 678-679 (2009).
Cunningham E, Drag M, Kafarski P, Bell A. Chemical target validation studies of aminopeptidase in malaria using alpha-aminoalkylphosphonate and phosphonopetide inhibitors. Antimicrob. Agents Chemother. 52:3221-3228 (2008).
Fennell BJ, Naughton JA, Barlow J, Brennan G, Fairweather I, Hoey E, McFerran N, Trudgett A, Bell A. Microtubules as antiparasitic drug targets. Expert Opin. Drug Discov. 3: 501-518 (2008).
Naughton JA, Hughes R, Bray PG, Bell A. Accumulation of the antimalarial microtubule inhibitors trifluralin and vinblastine by Plasmodium falciparum. Biochem. Pharmacol. 75: 1580-1587 (2008).
Fennell BJ, Al-shatr ZA, Bell A. Isotype expression, post-translational modification and stage-specific production of tubulins in erythrocytic Plasmodium falciparum. Int. J. Parasitol. 38: 527-539 (2008).
Walsh JJ, Coughlan D, Heneghan N, Gaynor C & Bell A. A Novel Artemisinin-Quinine Hybrid with Potent Antimalarial Activity. Bioorg, Med. Chem. Lett. 17: 3599-3602 (2007).
Naughton, J.A. & Bell, A. Studies on cell-cycle synchronization in the asexual, erythrocytic stages of Plasmodium falciparum. Parasitology 134: 331-7 (2007).
Gavigan, C.S., Shen, M., Machado, S.G. & Bell, A. Influence of the Plasmodium falciparum P-glycoprotein homologue 1 (pfmdr1 gene product) on the antimalarial action of cyclosporin. J. Antimicrob. Chemother. 59: 197-203 (2007).
Stack CM, Lowther J, Cunningham E, Donnelly S, Gardiner DL, Trenholme KR, Skinner-Adams TS, Teuscher F, Grembecka J, Mucha A, Kafarski P, Lua L, Bell A, Dalton JP. Characterisation of the Plasmodium falciparum M17 leucyl aminopeptidase: a protease involved in amino acid regulation with potential for antimalarial drug development. J. Biol. Chem. 282: 2069-80 (2007).
Bell , A., Monaghan, P., & Page, A.P. Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host–parasite interaction and antiparasitic drug action. Int. J. Parasitol. 36: 261-76 (2006).
Fennell, B.J., Naughton, J.A., Dempsey, E. & Bell, A. Cellular and molecular actions of dinitroaniline and phosphorothioamidate herbicides on Plasmodium falciparum: tubulin as a specific antimalarial target. Mol. Biochem. Parasitol. 145: 226-238 (2006).
Bell , A. Antimalarial drug synergism and antagonism: mechanistic and clinical significance. FEMS Microbiol. Lett. 253: 171-184 (2005).
Bell , A., Fennell, B.J., & Naughton, J.A. Microtubule assembly and disassembly as an antimalarial target: comme ci, comme ça. Parassitologia 47 (supp. 1): 32 (2005).
Monaghan, P., Fardis, M., Revill, W.P. & Bell, A. Anti-malarial effects of macrolactones related to FK520 (ascomycin) are independent of the immunosuppressive properties of the compounds. J. Infect. Dis. 191: 1342-1349 (2005).
Monaghan, P. & Bell, A. A Plasmodium falciparum FK506-binding protein (FKBP) with peptidyl-prolyl cis-trans isomerase and chaperone activities. Mol. Biochem. Parasitol . 139: 185-195 (2005).
Bell , A. & Machado, S.G. Assessing synergy or antagonism for drug combinations (letter). Nature Rev. Drug Discov . 3 (2004). http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrd/journal/v3/n6/corres/nrd1416_fs.html#c0
Gavigan, C.S. & Bell, A. A role for Pgh1 in the mechanism of antimalarial action of cyclosporins on Plasmodium falciparum. Exp. Parasitol., 105: 41 (2003).
Gavigan, C.S., Kiely, S.P., Hirtzlin, J. & Bell, A. Cyclosporin-binding proteins of Plasmodium falciparum . Int. J. Parasitol . 33: 987-996 (2003).
Mitchell, D.P. & Bell, A. PEST sequences in the malaria parasite Plasmodium falciparum : a genomic study. Malaria J. 2: 16 [5 pp] (2003).
Fennell, B. J., Carolan, S., Pettit, G.R. & Bell, A. Effects of the antimitotic natural product dolatstatin 10, and related peptides, on the human malarial parasite Plasmodium falciparum . J. Antimicrob. Chemother. 51: 833-841 (2003).
Gavigan, C.S., Dalton , J.P. & Bell, A. The role of aminopeptidases in haemoglobin degradation in Plasmodium falciparum -infected erythrocytes. Mol. Biochem. Parasitol. 117: 37-48 (2001).
Gavigan, C.S., Machado, S.G., Dalton , J.P. & Bell, A. Analysis of antimalarial synergy between bestatin and endoprotease inhibitors using statistical response-surface modeling. Antimicrob. Agents Chemother. 45: 3175-3181 (2001).
Bell , A. Recent developments in the chemotherapy of malaria. IDrugs 3: 310-317 (2000).
Bell , A., McSteen P.M., Cebrat, M., Picur, B. & Siemion, I.Z. Antimalarial activity of cyclolinopeptide A and its analogues. Acta Polon. Pharmaceut. - Drug Res . 57 (sup.): 134-136 (2000).
Bell , A. Recent developments in the chemotherapy of malaria. Curr. Op. Anti-infect. Invest. Drugs 2: 63-70 (2000).
Bell , A., Kiely, S.P., Keenan, M.C., & Hirtzlin, J. New strategies against malaria infections. Naunyn-Schmied. Arch. Pharmacol . 358: R758 (1998).
Nankya-Kitaka, M.F., Curley, G.P., Gavigan, C.S., Bell , A. & Dalton, J.P. Plasmodium chabaudi chabaudi and Plasmodium falciparum : inhibition of aminopeptidase and parasite growth by bestatin and nitrobestatin. Parasitol. Res . 84: 552-558 (1998).
Bell , A. Microtubule inhibitors as potential antimalarial agents. Parasitol. Today 14: 234-240 (1998).
Hirtzlin, J., Färber, P.M., Franklin, R.M. & Bell, A. Molecular and biochemical characterization of a Plasmodium falciparum cyclophilin. Ann. Trop. Med. Parasitol . 90: 430 (1996).
Bell , A., Roberts, H. C. & Chappell, L. H. The antiparasite effects of cyclosporin A: possible drug targets and clinical applications. Gen Pharmacol 27: 963-971 (1996).
Hirtzlin, J., Faerber, P.M., Franklin, R.M. & Bell, A. Molecular and biochemical characterization of a Plasmodium falciparum cyclophilin containing a cleavable signal sequence. Eur J Biochem 232 : 765-772 (1995).
Bell, A., Wernli, B. & Franklin, R. M. Expression and secretion of malarial parasite beta-tubulin in Bacillus brevis . Biochimie 77: 256-261 (1995).
Weyrauch, G., Zhao, Y., Bell, A., Franklin, R. M., & Kappes, B. Characterization of the junction domain of a calcium-dependent protein kinase from Plasmodium falciparum . Ann. Trop. Med. Parasitol. 89: 216 (1995).
Graeser, R., Bell, A., Franklin, R. M. & Kappes, B. Growth regulating kinases of Plasmodium falciparum . Ann. Trop. Med. Parasitol . 89: 179 (1995).
Bell , A., Wernli, B. & Franklin, R. M. Roles of peptidyl-prolyl cis-trans isomerase and calcineurin in the mechanisms of antimalarial action of cyclosporin A, FK506, and rapamycin. Biochem. Pharmacol. 48: 495-503 (1994).
Bell , A., Wernli, B. & Franklin, R. M. Effect of microtubule inhibitors on protein synthesis in Plasmodium falciparum . Parasitol. Res. 79: 146-152 (1993).