Chemokines are therefore inflammatory mediators released by macrophages at the site of infection to recruit more leukocytes to the area; by inhibiting chemokines inflammation can be prevented. With over 50 different chemokines and 20 different receptors in the chemokine system there is much redundancy. Consequently an inhibitor is needed that acts on multiple chemokine to have an effect, BSCIs inhibit five different chemokines; MCP-1, RANTES, MIP-1α, IL-8 and SDF-1α. The first BSCI 'peptide 3' was a dodecapeptide derived from MCP-1, the critical motif for activity was discovered to be the tripeptide WVQ and it is from this tripeptide that current BSCIs are based. The tryptophan and valine are varying length hydrophobic groups joined by an amide bond to a lactam which represents the glutamine.
WVQ, Early BSCI and Lactam containing BSCI
The group has discovered that BSCIs bind to the functionally selective receptor sstr2 commonly thought of as a somatostatin receptor. Somatostatin is a cyclic peptide hormone which functions as a growth hormone inhibitor when bound to sstr2.
Part of my work is concerned with synthesising a catalogue of molecules based on current sstr2 ligands, BSCIs and compounds which are hybrids of the two. The aim is to gain information on the critical motif of action for each function of the receptor.
sstr2 ligand, hybrid ligand and a BSCI
I have also synthesised a catalogue of BSCIs with varying length chains. This will allow us to determine whether and at what point our molecules become competitive with somatostatin at binding to sstr2. Finally I have synthesised some small BSCIs as potential drug candidates and some fluororescent molecules for binding studies.