Award details

Support for Chemical Biology at UCL

Reference	BB/C511413/1
Principal Investigator / Supervisor	Professor Stephen Caddick
Co-Investigators / Co-Supervisors	Professor Helen Hailes, Professor Alethea Tabor
Institution	University College London
Department	Chemistry
Funding type	Research
Value (£)	184,000
Status	Completed
Type	Research Grant
Start date	01/07/2005
End date	31/03/2006
Duration	9 months

Abstract

This proposal seeks support for several projects in the area of Chemical Biology in the Department of Chemistry at UCL. We are requesting funds for a MALDI-mass spectrometer and a microwave peptide synthesiser. These instruments will support the proposed research projects by enabling the analysis and characterisation of biological molecules and complexes (MALDI-MS). A significant proportion of the proposed work involves the synthesis of peptides and protein chemistry and the award of funds for a microwave peptide synthesiser will enable the rapid assembly of complex peptides. Summary of Projects.1. Fundamental investigations into the interaction of apo-Neocarzinostatin (apoNCS) with synthetic ligands and chemical modification of the NCS apoprotein. NCS is a natural product comprising a small molecule non-covalently bound to an apo-protein and has found clinical use in Japan (cancer). This project involves the synthesis of novel anchor ligands and their complexation with the apoprotein. The long-term aim is to attempt to attach known pharmaceuticals to novel anchor systems to enable their recruitment into the apo-NCS binding site. This will enable us to explore the delivery of pharmaceuticals in vivo. In order to further support this aim we also propose to attach fluorophores to apo-NCS using protein modification. Finally we also propose to carry out the synthesis of apoNCS using ligation approaches, which will enable the introduction, for example of isotopically labelled peptides into the binding site of the apoprotein. 2. Development of new anti-tuberculosis chemotherapeutics. Tuberculosis (TB) results in approximately 3 million deaths each year. Several years ago it was reported that a heterogeneous mixture of calixarenes had a profound suppressive effect on the growth of M. tuberculosis. Reactive nitrogen intermediates have recently been implicated in the mechanism of action of these compounds and we will probe the role of NO with the synthesis of the calix[8]arenes and calix[6]arenes possessing pendant hydrophobic and hydrophilic thiol groups using the methodology established in our group. These compounds will be used in complexation studies (NMR) with NO+, and tested in vivo. 3. Total synthesis of lantibiotics, on resin, via a multiply orthogonal protecting group strategy. The lantibiotics are a family of highly complex peptide antibiotics but there is little known about their mode of action. This is because of the lack of synthetic methods available. On the basis of extensive previous published work from the Tabor group we propose to: (I) Develop a synthesis of orthogonally protected methyllanthionine, based on the regioselective ring-opening of threonine-derived aziridines bearing sterically bulky ester protecting groups; (II) Develop a quadruply-orthogonal protecting group strategy for the on-resin synthesis of peptides with multiple overlapping thioether bridges; (III) Apply these methods to the synthesis of a model for rings D and E of nisin. 4. Development of new lipids, peptides and lipid-peptide conjugates for gene therapy. Gene therapy, where small pieces of DNA are delivered into the appropriate target cells to replace the malfunctioning genes will be of enormous benefit in the treatment of many diseases. There are two aspects to this project currently underway: (a) Exploration of the interaction between the peptide and lipid via the synthesis of lipid-peptide conjugates. A range of analogues will be explored with both cleavable and non-cleavable linkages to enable the effect of late, early or non-dissociation of these compounds on transfection efficiencies to be studied. (b) Use of targeted peptides with endosomally cleavable targeting moieties and PEG or hydrophobic spacers. We will use structurally defined PEGylaged lipids possessing endosomally cleavable PEG units, and cell-specific receptor targeted peptides with endosomally cleavable targeting moieties and complementary PEG units. In this REI project we aim to: synthesise receptor targeted peptides with endosomally cleavable targeting moieties and PEG or hydrophobic spacers; test the cleavage properties of these components under endosomal conditions.

Summary

unavailable

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Research Equipment Initiative 2004 (RE4) [2004]
Funding Scheme	X – not Funded via a specific Funding Scheme

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