Research Activities – Associate Professor Angus Bell

MALARIA

Angus Bell, BSc (Hons.) MA PhD FTCD– Senior Lecturer and SS Research Project Coordinator in Microbiology.

E-mail: abell@tcd.ie

• Malaria remains one of the world’s most important parasitic diseases. 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 of malaria more and 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 with a view to the development of novel antimalarial drugs. The major, current interests lie in malaria research that is both basic (especially the microtubular system, immunophilins, and the haemoglobin degradation pathway) and applied (mechanisms of action of cyclosporin A, FK506 and related non-immunosuppressive agents; new drug design; mechanisms of drug resistance). The group has worldwide collaborations, especially with chemists interested in antimalarial drug development and with scientists in malaria-endemic countries.

Research Personnel

Research Fellows:
Dr. D. Boehm boehmd@tcd.ie

Postgraduate Researchers:
Mr. F. Doyle doylef4@tcd.ie
Mr. D. Leneghan leneghad@tcd.ie
Ms. Alessandra Bianchin (joint with Prof. Denis Shields & Dr. Anthony Chubb, University College Dublin) Alessandra.Bianchin@ucdconnect.ie

Malaria Research Group Publications

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).

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).

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).