Senior Lecturer in Medicinal Chemistry
5 West – 3.8
Tel: +44 (0) 1225 383101
Dr Ian M. Eggleston
Our research focuses on the design and delivery of drugs. We are particularly interested in the application of peptide chemistry to problems in biology and medicine, and therapeutic strategies using light. Recent and current work is in collaboration with colleagues at University College London, Dundee, and Bath, with funding from BBSRC, Wellcome Trust, and the British Skin Foundation.
Chitin is an essential component of fungal cell wells, nematode egg shells and arthropod skeletons. We have synthesised various potent and selective inhibitors of family 18 chitinases, which degrade this biopolymer, including natural product-inspired peptides and some novel “dicaffeines” that are selective ligands for chitinases and other carbohydrate-binding proteins. These molecules have potential as antifungals, antiparasitic agents, and mediators of allergic inflammation and asthma.
Peptide-targeted agents for PDT and photobiology
In photodynamic therapy (PDT), destruction of tumours or pathogens is achieved with light after selective administration of a light-activated photosensitising drug. Treatment with 5-aminolaevulinic acid (ALA), a precursor of the natural photosensitiser, protoporphyrin IX, is a promising strategy in PDT, and we are currently developing ALA-containing peptide prodrugs with enhanced cellular uptake and targeting properties. We are also interested in using peptide-targeted photosensitisers for drug delivery, by photochemical internalisation (PCI). In PCI, delivery of cancer therapeutics, macromolecular drugs, and imaging agents may be enhanced at specific sites, by illuminating the relevant tissue in conjunction with a suitable photosensitiser.
Light-activated caged iron chelators
We are synthesising caged iron chelators - prodrugs in which a key iron-binding function of a chelator is masked with a photolabile group. These molecules are then activated to bind iron only upon exposure to a specific light dose, avoiding toxic side-effects that are associated with the prolonged administration of strong iron chelators. Their potential as UVA photoprotectants, and targeted therapeutics for iron-dependent disorders is being evaluated.
Houshmandyar, S., Reelfs, O., Radka, T., Eggleston, I. and Pourzand, C., 2016. Deferiprone And Deferasirox As Promissing Candidate Ligands For Skin Photoprotection By Light-Activated Caged-Iron Chelators. American Journal of Hematology, 91 (3), E69-E69.
Godfrey, S., Sarpaki, S., Mirabello, V., Eggleston, I. and Pascu, S., 2016. Design and synthesis of porphyrin-based metal complexes for multimodal bioimaging. Journal of Labelled Compounds & Radiopharmaceuticals, 59 (4), p. 183.
Taverner, A., Dondi, R., Almansour, K., Laurent, F., Owens, S.-E., Eggleston, I. M., Fotaki, N. and Mrsny, R. J., 2015. Enhanced paracellular transport of insulin can be achieved via transient induction of myosin light chain phosphorylation. Journal of Controlled Release, 210, pp. 189-197.
Hu, Z., Arrowsmith, R. L., Tyson, J. A., Mirabello, V., Ge, H., Eggleston, I. M., Botchway, S. W., Pantos, D. and Pascu, S. I., 2015. A fluorescent Arg–Gly–Asp (RGD) peptide–naphthalenediimide (NDI) conjugate for imaging integrin αvβ3in vitro. Chemical Communications, 51 (32), pp. 6901-6904.
Alade, A., Yaghini, E., Dondi, R., Eggleston, I. and MacRobert, A. J., 2015. The cell-penetrating peptide chlorin conjugate, a novel class of photosensitiser for photodynamic therapy and photochemical internalisation. British Journal of Surgery, 102 (S5), p. 36.
Di Venosa, G., Vallecorsa, P., Giuntini, F., Mamone, L., Batlle, A., Vanzuli, S., Juarranz, A., MacRobert, A. J., Eggleston, I. M. and Casas, A., 2015. The use of dipeptide derivatives of 5-aminolaevulinic acid promotes their entry to tumor cells and improves tumor selectivity of photodynamic therapy. Molecular Cancer Therapeutics, 14 (2), pp. 440-451.
Reelfs, O., Young, B., Radka, T., Eggleston, I. and Pourzand, C., 2014. A novel generation of photoactivatable caged-iron chelators with both antioxidant and iron chelation properties for skin photoprotection. In: European Iron Club 2014, 2014-09-11 - 2014-09-14.
Radka, T., Reelfs, O., Dondi, R., Eggleston, I. and Pourzand, C., 2014. UVA-activatable caged iron chelators significantly improve the efficiency of topical aminolevulinate-based photodynamic therapy of skin cancer.
Yaghini, E., Giuntini, F., Eggleston, I. M., Suhling, K., Seifalian, A. M. and MacRobert, A. J., 2014. Fluorescence lifetime imaging and FRET-induced intracellular redistribution of tat-conjugated quantum dot nanoparticles through interaction with a phthalocyanine photosensitiser. Small, 10 (4), pp. 782-792.
Jolly, P., Formisano, N., Djahanbakhsh Rafiee, S., Bhalla, N., Miodek, A., Dondi, R., Yang, D. K., Chen, L.C., Kasak, P., Tkac, J., Lloyd, M. D., Eggleston, I. M. and Estrela, P., 2014. DNA aptamer-based approaches for detection of multiple prostate cancer biomarkers. In: 22nd Meeting of the EAU Section of Urological Research (ESUR), 2014, 2014-10-09 - 2014-10-11.
Arrowsmith, R., Kociok-Kohn, G., Eggleston, I., Tyrrell, R., Dilworth, J. R., Aigbirhio, F. I. and Pascu, S., 2014. Intrinsically fluorescent bis(thiosemicarbazonates) with high kinetic stability in biological environments: synthetic scaffolds for optical/PET or SPECT dual-modality imaging agent. Journal of Labelled Compounds & Radiopharmaceuticals, 57 (3), pp. 189-190.
Pourzand, Charareh, 2014. Preparation of UV radiation cleavable compounds. PCT Int. Appl.- WO 2014041362, 2014.
Reelfs, O., Young, B., Aroun, A., Hoffmann, M., Miri, S. A., Richardson, D. R., Eggleston, I. and Pourzand, C., 2013. A comparative study of the antiprolifrative activity of thiosemicarbazone iron chelators in skin cells. American Journal of Hematology, 88 (5), E170-E170.
Radka, T., Reelfs, O., Dondi, R., Eggleston, I. and Pourzand, C., 2013. Improving the efficiency of aminolevulinate-photodynamic therapy of skin cancer by combining uva irradiation and potent iron chelating agents. American Journal of Hematology, 88 (5), E170-E171.
Young, B., Reelfs, O., Aroun, A., Eggleston, I. and Pourzand, C., 2013. Light-activatable and photo-controlled caged-nih, a promising pro-iron chelator for the topical therapy of skin cancer. American Journal of Hematology, 88 (5), E177-E177.
Young, B., Reelfs, O., Aroun, A., Miri, S. A., Hoffmann, M., Pourzand, C. and Eggleston, I., 2013. Novel light-activated caged iron chelators: targeted prodrugs for iron related-disorders. American Journal of Hematology, 88 (5), E176-E176.
Schimpl, M., Rush, C. l., Betou, M., Eggleston, I. M., Recklies, A. d. and Van aalten, D. m. F., 2012. Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties. Biochemical Journal, 446 (1), pp. 149-157.
Wang, J. T. -W., Giuntini, F., Eggleston, I. M., Bown, S. G. and MacRobert, A. J., 2012. Photochemical internalisation of a macromolecular protein toxin using a cell penetrating peptide-photosensitiser conjugate. Journal of Controlled Release, 157 (2), pp. 305-313.
van Aalten, Daan M. F., 2012. New xanthine compounds useful as aspergillus fumigatus chitinase B1 inhibitors to prevent/treat e.g. asthma, autoimmune disease and fungal infections. WO2006136822-A1; EP1893614-A1; JP2008546752-W; US2009215798-A1; US8207175-B2; EP1893614-B1, 2012.
Arrowsmith, R. L., Zeglis, B. M., Viola-Villegas, N., Divilov, V., Jones, M., Waghorn, P. A., Phillips, F. L., Mindt, T. L., Eggleston, I. M., Botchway, S. W., Dilworth, J. R., Aigbirhio, F. I., Lewis, J. S. and Pascu, S. I., 2011. Fluorescent copper(II), gallium(III) and indium(III) bis(thiosemicarbazonates):Radiolabeling, cellular confocal fluorescence and PET imaging studies. Journal of Labelled Compounds & Radiopharmaceuticals, 54 (Supplement 1), S59.
Sutherland, T. E., Andersen, O. A., Betou, M., Eggleston, I. M., Maizels, R. M., van Aalten, D. and Allen, J. E., 2011. Analyzing airway inflammation with chemical biology: Dissection of acidic mammalian chitinase function with a selective drug-like inhibitor. Chemistry & Biology, 18 (5), pp. 569-579.
Webb, C., Upadhyay, A., Giuntini, F., Eggleston, I., Furutani-Seiki, M., Ishima, R. and Bagby, S., 2011. Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway. Biochemistry, 50 (16), pp. 3300-3309.
Schuettelkopf, A. W., Andersen, O. A., Rao, F. V., Allwood, M. B., Rush, C., Eggleston, I. and van Aalten, D. M. F., 2011. Bisdionin C-A Rationally Designed, Submicromolar Inhibitor of Family 18 Chitinases. ACS Medicinal Chemistry Letters, 2 (6), p. 428.
Rush, C. L., Schuttelkopf, A. W., Hurtado-Guerrero, R., Blair, D. E., Ibrahim, A. F. M., Desvergnes, S., Eggleston, I. M. and van Aalten, D. M. F., 2010. Natural Product-Guided Discovery of a Fungal Chitinase Inhibitor. Chemistry & Biology, 17 (12), pp. 1275-1281.
Reelfs, O., Eggleston, I. M. and Pourzand, C., 2010. Skin protection against UVA-induced iron damage by multiantioxidants and iron chelating drugs/prodrugs. Current Drug Metabolism, 11 (3), pp. 242-249.
Bourre, L., Giuntini, F., Eggleston, I. M., Mosse, C. A., MacRobert, A. J. and Wilson, M., 2010. Effective photoinactivation of Gram-positive and Gram-negative bacterial strains using an HIV-1 Tat peptide-porphyrin conjugate. Photochemical & Photobiological Sciences, 9 (12), pp. 1613-1620.
Giuntini, F., Bourre, L., MacRobert, A. J., Wilson, M. and Eggleston, I. M., 2009. Improved peptide prodrugs of 5-ALA for PDT: rationalization of cellular accumulation and protoporphyrin IX production by direct determination of cellular prodrug uptake and prodrug metabolization. Journal of Medicinal Chemistry, 52 (13), pp. 4026-4037.
Higgins, L. G., Kelleher, M. O., Eggleston, I. M., Itoh, K., Yamamoto, M. and Hayes, J. D., 2009. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents. Toxicology and Applied Pharmacology, 237 (3), pp. 267-280.
Dixon, M. J., Nathubhai, A., Andersen, O. A., van Aalten, D. M. F. and Eggleston, I. M., 2009. Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold. Organic and Biomolecular Chemistry, 7 (2), pp. 259-268.
Kelleher, M. O., McMahon, M., Eggleston, I. M., Dixon, M. J., Taguchi, K., Yamamoto, M. and Hayes, J. D., 2009. 1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxicα,β-unsaturated aldehyde acrolein. Carcinogenesis, 30 (10), pp. 1754-1762.
Bourre, L., Giuntini, F., Eggleston, I. M., Wilson, M. and MacRobert, A. J., 2009. Protoporphyrin IX enhancement by 5-aminolaevulinic acid peptide derivatives and the effect of RNA silencing on intracellular metabolism. British Journal of Cancer, 100 (5), pp. 723-731.
Dixon, M. J., Andersen, O. A., van Aalten, D. M. F. and Eggleston, I. M., 2009. SPPS of the natural product chitinase inhibitor argifin: library generation and biological evaluation. In: Del Valle, S., Escher, E. and Lubell, W. D., eds. Peptides for Youth.Vol. 611. New York: Springer, pp. 143-144.
Dixon, M. J., Nathubhai, A., Andersen, O. A., van Aalten, D. M. F. and Eggleston, I. M., 2009. Synthesis and Structure-based Dissection of Cyclic Peptide Chitinase Inhibitors: New Leads for Antifungal and Anti-inflammatory Drugs. In: DelValle, S., Escher, E. and Lubell, W. D., eds. Peptides for Youth - The Proceedings of the 20th American Peptide Symposium. Springer, pp. 525-526.
Giuntini, F., Bourre, L., MacRobert, A. J., Wilson, M. and Eggleston, I. M., 2008. Quantitative determination of 5-aminolaevulinic acid and its esters in cell lysates by HPLC-fluorescence. Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences, 875 (2), pp. 562-566.
Giuntini, F., Bourre, L., Wilson, M., MacRobert, A. J. and Eggleston, I. M., 2008. A novel approach to improve cellular delivery of 5-aminolaevulinic acid:New ALA-containing peptide prodrugs for photodynamic therapy. Journal of Peptide Science, 14 (8 (Suppl S)), p. 156.
Dixon, M., Giuntini, F., Nathubhai, A., Andersen, O., van Aalten, D. and Eggleston, I., 2008. Synthetic approaches to cyclic peptide natural products as chitinase inhibitors. Journal of Peptide Science, 14 (8), p. 55.
Andersen, O. A., Nathubhai, A., Dixon, M. J., Eggleston, I. M. and van Aalten, D. M. F., 2008. Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin. Chemistry & Biology, 15 (3), pp. 295-301.
Bourre, L., Giuntini, F., Eggleston, I. M., Wilson, M. and MacRobert, A. J., 2008. 5-aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy. Molecular Cancer Therapeutics, 7 (6), pp. 1720-1729.
Paterson, M. J. and Eggleston, I. M., 2008. Convenient preparation of N-maleoyl amino acid succinimido esters using N-trifluoroacetoxysuccinimide. Synthetic Communications, 38 (2), pp. 303-308.
Dixon, M., Nathubhai, A., Andersen, O., van Aalten, D. and Eggleston, I. M., 2008. Synthesis of cyclic peptide chitinase inhibitors:Natural products,with chemotherapeutic potential. Journal of Peptide Science, 14 (8 (Suppl S)), p. 13.
Hayes, J. D., Kelleher, M. O. and Eggleston, I. M., 2008. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. European Journal of Nutrition, 47, pp. 73-88.