Dr Karen Grant
Senior Lecturer (Lancaster Medical School)
Office Faraday C12
Centre for Medical Education
Lancaster University, LA1 4YA
Tel: +44 1524 594521
Department of Biological Sciences
Lancaster University, LA1 4YQ
Tel: +44 1524 593688
Fax: +44 1524 593192
Iím primarily interested in the protozoan parasites, Leishmania and Trypanosoma, the infective agents in leishmaniasis and African sleeping sickness respectively. Specifically, Iím interested in the interface between biology and chemistry and the translation of advances in basic biology into the development of novel drugs against these parasitic diseases.
The leishmaniases are a group of diseases, prevalent in the tropics and sub-tropics. They include life-threatening visceral leishmaniasis, cutaneous leishmaniasis, the most common form of the disease, and the seriously disfiguring muco-cutaneous leishmaniasis. The WHO estimate that 12 million people are affected by leishmaniasis in 88, predominantly developing, countries worldwide.
African sleeping sickness affects 36 countries in sub-Saharan Africa. Infection with Trypanosoma parasites results initially in malaise, lethargy and intermittent fever leading to coma and death if the infection spreads to the central nervous system. At present, African sleeping sickness claims relatively few lives but there is a continued threat of a major epidemic, which would a devastating effect on affected areas.
Current first-line chemotherapies for leishmaniasis and African sleeping sickness are far from ideal. They are not particularly effective, have serious toxic side effects and drug resistance is an increasing problem. Thus there is an urgent need for new drugs against these tropical parasitic diseases.
Work within my laboratory aims to identify and validate novel drug targets, using a combination of molecular biology and classical biochemistry, with a particular interest in protein kinase enzymes and cell cycle control. Previous work validated a leishmanial cyclin-dependent kinase (CDK), CRK3, as a potential drug target and identified CDK inhibitors which had anti-parasitic activity in vitro. In collaboration with synthetic chemists, we are now working towards optimizing these CRK3 inhibitors using a variety of different approaches, including classical chemical derivatisation and model-based rational drug design. This latter involves preparing a model of the 3D structure of CRK3, identifying significant differences from its mammalian counterpart(s) and then exploiting these differences to design parasite-selective inhibitors. Recombinant protein technology is used to provide active enzyme for chemical library screening and for X-ray crystallography.
Development of Parasite-selective Indirubin CDK-inhibitors:
In collaboration with the organic synthetic chemist, Dr Nick Westwood, University of St Andrews.
The indirubin family of CDK inhibitors have already been shown to be potent but non-selective inhibitors of leishmanial CRK3 and to have anti-leishmanial activity in vitro. This project aims to use molecular modelling and rational drug design to develop parasite-selective inhibitors around the indirubin pharmacophore and to assay their biological activity, with a view to developing a novel anti-leishmanial chemotherapy.
Development of a pan-trypanosomatid CDK inhibitor:
This is a multi-centred collaborative project which integrates chemistry and biology and links academia and industry. It aims to use a number of different approaches to discover, design, develop small molecule inhibitors of CRK3 from the 2 parasitic protozoa: Leishmania (leishmaniasis) and T.brucei (African sleeping sickness), with the view to develop a novel chemotherapy which would treat both of these important parasite diseases. Approaches include screening CRK3 against a 30,000+ chemical library (with the biopharmaceutical company, Cyclacel); in silico screening for novel pharmacophores for CRK3 inhibitors (followed up by synthesis of interesting lead compounds); generating an X-ray crystal structure of CRK3 in complex with various small molecule inhibitors.
Bioinformatics have identified 6 putative casein kinase 1 (CK1) homologues in Leishmania major. In other eukaryotes, CK1s play important roles in many diverse systems including: DNA repair, cell cycle control and membrane-trafficking. This project, in collaboration with colleagues at Keele University, is at the preliminary stage, elucidating the role of these protein kinases in the parasite with the view to validating it as a potential drug target.
- B.Sc. (Hons) Pharmacy, University of Strathclyde
- Ph.D. Pharmaceutical Sciences, University of Strathclyde
- 1993 -1994 Post-doctoral Research Assistant, Institute of Genetics, University of Glasgow
- 1994-1997 Post-doctoral Research Assistant, Wellcome Unit of Molecular Parasitology, University of Glasgow
- 1999-2001 Post-doctoral Research Associate, Wellcome Centre for Molecular Parasitology, University of Glasgow
- 2002-2004 Post-doctoral Research Associate, Wellcome Centre for Molecular Parasitology, University of Glasgow
- 2004-2007 Lecturer in Biomedical Science, School of Medicine/School of Life Sciences, Keele University
- 2006-present Senior Lecturer, Centre for Medical Education, Lancaster University
Grant, K.M., Dunion, M.H., Yardley, V., Skaltsounis, A-L., Marko, D., Eisenbrand, G., Croft, S L., Meijer, L. and Mottram, J.C. (2004) “Inhibitors of Leishmania mexicana CRK3 cyclin-dependent kinase: chemical library screen and anti-leishmanial activity&rdquo Antimicrob. Agents Chemother. 48 3033-3042 [Full Text]
Knockaert, M., Wiking, K., Schmitt, S., Leost, M., Grant, K.M., Mottram, J.C., Kunick, C. and Meijer, L. (2002) “Intracellular targets of paullones: identification by affinity chromatography using immobilized inhibitor” J. Biol. Chem. 277 25493-25501 [Full Text]
Hassan,P., Fergusson, D., Grant,K.M., and Mottram,J.C. (2001) “The CRK3 protein kinase is essential for cell cycle progression of Leishmania mexicana” Mol Biochem. Parasitol. 113 189-198 [Pubmed]
Knockaert,M., Gray,N., Damiens,E., Chang,Y.-T., Grellier,P., Grant,K.M., Fergusson,D., Mottram,J.C., Soete,M., Le Roch,K., Doerig,C., Schultz,P.G., and Meijer,L. (2000) “Intracellular targets of cyclin-dependent kinase inhibitors: identification by affinity chromatography using immobilised inhibitors” Chemistry & Biology 7 411-422 [Full Text]
Grant, K.M., Hassan, P., Anderson, J.S. and Mottram, J.C. (1998) “The crk3 gene of Leishmania mexicana encodes a stage-regulated cdc2-related histone H1 kinase that associates with p12cks1” J. Biol. Chem. 273 10153-10159 [Full Text]
Mottram, J.C. and Grant, K.M. (1996) “Leishmania mexicana p12cks1, a homologue of fission yeast p13suc1, associates with a stage regulated histone H1 kinase” Biochem. J. 316 833-839 [Full Text]
Mottram, J.C., McCready, B.P., Brown, K.G. and Grant, K.M. (1996) “Gene disruptions indicate an essential function for the LmmCRK1 cdc2-related kinase of Leishmania mexicana” Mol. Micro. 22 573-582 [Full Text]
Wells, C., I. McNae, M. Walkinshaw, N. J. Westwood, and K. M. Grant (2006) “The selective biological activity of indirubin-based inhibitors: applications in parasitology” p. 259-267 In: L. Meijer, N. Guyard, A. L. Skaltsounis, and G. Eisenbrand (eds.), Indirubin, the red shade of indigo. Life in Progress Editions, Roscoff, France. ISBN: 2-9518029-0-0
Hurd, H., Grant, K.M., Arambage, S.C. (2006) “Apoptosis-like death as a feature of malaria infection in mosquitoes” Parasitology 132 Suppl:S33-47 [Pubmed]