Skip to main content

New chemical biology for tailoring novel therapeutics

Objective

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.

Call for proposal

ERC-2013-ADG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Address
Wellington Square University Offices
OX1 2JD Oxford
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 042 087,45
Principal investigator
James Henderson Naismith (Prof.)
Administrative Contact
Gill Wells (Ms.)

Beneficiaries (3)

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
EU contribution
€ 1 042 087,45
Address
Wellington Square University Offices
OX1 2JD Oxford
Activity type
Higher or Secondary Education Establishments
Principal investigator
James Henderson Naismith (Prof.)
Administrative Contact
Gill Wells (Ms.)
THE UNIVERSITY COURT OF THE UNIVERSITY OF ABERDEEN
United Kingdom
EU contribution
€ 525 761,60
Address
King's College Regent Walk
AB24 3FX Aberdeen
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Crystal Anderson (Ms.)
THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS

Participation ended

United Kingdom
EU contribution
€ 932 141,95
Address
North Street 66 College Gate
KY16 9AJ St Andrews
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Trish Starrs (Ms.)