Obiettivo Most of our drugs derive from natural products, many more natural products possess biological activity but our inability to synthesise novel analogues hampers our ability to use them either as tools or medicines. Cyclic peptides are common structural motifs in natural products and medicines (vancomycin, gramicidin). They are widely recognised to constitute a promising and still underexploited class of molecule for novel therapeutics; specifically an important role for cyclic peptides in the inhibition of protein-protein interactions has been demonstrated. We will harness the power of the recently identified macrocyclases from the ribosomally-derived cyanobactin superfamily to prepare diverse modified cyclic peptides. These enzymes exhibit the remarkable ability to macrocyclise unactivated peptide substrates. Different members of this family of macrocyclases process peptides into macrocycles containing from six up to twenty residues. We have characterised and re-engineered one member of the family (PatG) which makes eight residue macrocycles. We will determine the structural and biochemical features of the macrocyclases that are known to lead to six or to twenty residue macrocycles. We will use these insights to put these enzymes to work in novel chemical reactions. We will combine macrocyclases with other enzymes from the cyanobactin biosynthetic pathways (whose structures and mechanism we have largely determined) and work on solid phase peptide substrates. By bringing together the power of solid phase methods (split and pool) and the novel chemistry enabled by the enzymes, we will generate highly diverse macrocyclic scaffolds containing amino acids, enzymatically modified amino acids, non-natural amino acids and non-amino acid building blocks. Successful completion of the project will revolutionise the design of cyclic peptide-inspired libraries with diverse backbone scaffolds for applications in target identification, drug discovery and tool screening. Campo scientifico medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural scienceschemical sciencesorganic chemistryaminesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programma(i) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) ERC-AG-LS1 - ERC Advanced Grant - Molecular and Structural Biology and Biochemistry Invito a presentare proposte ERC-2013-ADG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-AG - ERC Advanced Grant Istituzione ospitante THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Contributo UE € 1 042 087,45 Indirizzo WELLINGTON SQUARE UNIVERSITY OFFICES OX1 2JD Oxford Regno Unito Mostra sulla mappa Regione South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Tipo di attività Higher or Secondary Education Establishments Ricercatore principale James Henderson Naismith (Prof.) Contatto amministrativo Gill Wells (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Beneficiari (3) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Regno Unito Contributo UE € 1 042 087,45 Indirizzo WELLINGTON SQUARE UNIVERSITY OFFICES OX1 2JD Oxford Mostra sulla mappa Regione South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Tipo di attività Higher or Secondary Education Establishments Ricercatore principale James Henderson Naismith (Prof.) Contatto amministrativo Gill Wells (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato THE UNIVERSITY COURT OF THE UNIVERSITY OF ABERDEEN Regno Unito Contributo UE € 525 761,60 Indirizzo KING'S COLLEGE REGENT WALK AB24 3FX ABERDEEN Mostra sulla mappa Regione Scotland North Eastern Scotland Aberdeen City and Aberdeenshire Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Crystal Anderson (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS Partecipazione conclusa Regno Unito Contributo UE € 932 141,95 Indirizzo NORTH STREET 66 COLLEGE GATE KY16 9AJ St Andrews Mostra sulla mappa Regione Scotland Eastern Scotland Clackmannanshire and Fife Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Trish Starrs (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato