School of Medical Sciences


Optimised enzymes for prodrug activating gene therapy

Project Leaders


mutatgenesis
Targeted mutagenesis of nitroreductase based on HotSpot wizard and molecular modelling


Translational Therapeutics Main Page
Bioreductive Prodrugs Main Page
Molecular Modelling Main Page

Bacterial nitroreductase (NTR) enzymes are efficient catalysts of aerobic (2e) nitroaromatic reduction. In collaboration with Dr David Ackerley we have identified novel NTRs able to activate the clinical-stage chemotherapeutic prodrug PR-104A as well as novel prodrugs developed in collaboration with Dr Jeff Smaill. As part of this collaboration we are also focused on improving these enzymes through a process known as directed evolution, whereby artificially accelerated improvements in enzyme function are achieved. Molecular modelling performed by Dr Jack Flanagan is used to help guide the selection of amino acid residues.

Collaborators: Dr David Ackerley

Keywords: NitroreductasesPR-104

Related publications


Prosser, G.A., Copp, J.N., Syddall, S.P., Williams, E.M., Smaill, J.B., Wilson, W.R., Patterson, A.V., Ackerley, D.F. Discovery and evaluation of Escherichia coli nitroreductases that activate the anti-cancer prodrug CB1954. Biochemical Pharmacology 2010; 79: 678-687. (PMID:19852945)

Prosser, G.A., Patterson, A.V., Ackerley, D.F. uvrB deletion enhances SOS chromatest sensitivity from nitroreductases that preferentially generate the 4-hydroxylamine metabolite of the anti-cancer dru CB1954. Journal of Biotechnology 2010; 150 (1): 150-154. (PMID:20727918)

Singleton, D.C., Li, D., Bai, S.C., Syddall, S.P., Smaill, J.B., Shen, Y., Denny, W.A., Wilson, W.R., Patterson, A.V. The nitroreductase prodrug SN28343 enhances the potency of the systemically administered armed oncolytic adenovirus ONYX-411NTR .Cancer Gene Therapy 2007,; 14: 953-967. (PMID:17975564)

Liu, S.C., Ahn, G.O., Kioi, M., Dorie, M.J., Patterson, A.V., Brown, J.M. Optimised Clostridium-directed enzyme prodrug therapy improves the antitumour activity of the novel DNA crosslinking agent PR-104. Cancer Research 2008; 68: 7995-8003. (PMID:18829557)