Dr Ian M. Eggleston

Profile

The general focus of our research is in synthetic organic chemistry and its application to problems in biology and medicine. We are particularly interested in the preparation of biologically active peptides and polyamines, and other small molecules as novel inhibitors or mechanistic probes for enzymes that are targets of therapeutic importance in the field of antifungals, asthma, and tropical disease. We also work on peptide-based prodrugs for use in selective light-activated treatment of cancer and infectious diseases, and have a longstanding interest in the anticarcinogenic properties of phytochemicals. Some of our current research projects include:

Chitinases and Carbohydrate Esterases

Chitin, a polymer of beta(1,4)-N-acetylglucosamine, is an essential structural component of fungal cell walls, nematode egg shells and arthropod exoskeletons. Family 18 chitinases, which degrade this polymer, have recently been validated as attractive targets for the development of inhibitors with chemotherapeutic potential against pathogenic fungi, insects and protozoan/nematodal parasites, and possibly inflammatory disorders such as asthma. We have recently synthesised two families of cyclic peptide natural products which have been identified as potent chitinase inhibitors, and in collaboration with the group of Prof. Daan van Aalten (University of Dundee), we are working on the X-ray structure-based design of novel inhibitors derived from these scaffolds, as well other drug-like chitinase inhibitors, based on a “dicaffeine” motif.

Family 4 carbohydrate esterases are enzymes that de-N-acetylate carbohydrate polymers such as chitin in the cell walls of microbial pathogens. This may allow these organisms to evade the action of carbohydrate-processing enzymes from the human immune system. In collaboration with Prof. van Aalten, we are also preparing chemical probes for these enzymes, in order to better understand their mechanisms and functions.

Trypanothione Reductase Inhibitors

Trypanothione reductase is an important, validated target for the design of new drugs to combat tropical parasitic diseases such as African sleeping sickness, Chagas’ disease, and leishmaniasis. We have synthesised various polyamine derivatives, based on natural product leads which have been screened for anti-TryR activity in collaboration with the group of Prof. Alan Fairlamb in Dundee. Some of these show significant in vitro antitrypanosomal activity and may serve as leads for developing new antitrypanosomal agents. We are also interested in polyamine-based inhibitors of other trypanothione-dependent enzymes which may be potential drug targets in antiparasitic chemotherapy.

Novel Peptide Prodrugs for ALA-PDT

Photodynamic therapy (PDT) is an emerging therapy for the treatment of cancer and various other human disorders. In PDT, destruction of tumours or pathogenic organisms is achieved with light following the administration of a light-activated photosensitising drug which is ideally selectively retained in, or targeted to, diseased tissue relative to normal adjacent tissue. The exogenous administration of 5-aminolaevulinic acid (ALA) has attracted considerable interest for PDT since it is a naturally occurring compound present in prokaryotic and eukaryotic cells which can be metabolised to a porphyrin photosensitiser, protoporphyrin IX (PpIX) via the haem biosynthetic pathway. ALA-PDT is a powerful approach for both the detection and treatment of cancers, and also has considerable potential for use in antimicrobial applications since various Gram-positive and Gram-negative bacteria, yeasts and fungi are able to assimilate exogenous ALA for porphyrin synthesis, thus rendering them susceptible to photosensitisation. A key challenge in ALA-PDT is to improve the efficiency of ALA delivery, since the zwitterionic nature of ALA itself at physiological pH limits its passage through cellular membranes and other biological barriers. The selective delivery and release of ALA in specific tissues is also currently difficult to achieve. In collaboration with Dr Sandy MacRobert and Professor Michael Wilson (University College London), we are preparing novel ALA-containing peptide prodrugs with improved cellular uptake and targeting properties and investigating the effectiveness of these compounds in a variety of cell lines and microorganisms.

Publications

View more publications »