Synthesis and Study of Oxetane Modified Peptides

EPSRC Key Research Ares - Chemical biology and biological chemistry and Synthetic organic chemistry

Peptides and their larger counterparts, proteins, are assembled by linking together the proteinogenic amino acids through identical, repeating amide (peptide) bonds. These oligomeric structures produce incredible levels of structural diversity that ultimately enables great variety in biological function. Peptides and proteins have evolved to fulfill critical functions in almost all processes in cells, and consequently they are important molecules in drug discovery. Chemical modification of a peptide can improve its usefulness as a potential drug by increasing its bioavailability, serum half-live or enhance selectivity for the target receptor. Molecules that mimic the structure or action of a natural peptide are broadly defined as peptidomimetics, and are themselves very useful in drug discovery. Here, we seek to develop a completely new type of peptidomimetic, in which the heterocyclic oxetane nucleus is used as a replacement for the C=O group of the amide bond. This substitution should reduce the vulnerability of the molecules to cleavage by peptidases/proteases (increasing their bioavailability), and produce intriguing changes to the conformation and properties of the peptides. Practical methods for the synthesis of oxetane modified peptides (OMPs), in which site selective replacement of the carbonyl group of one or more of the proteinogenic amino acids along the backbone, will be developed. Using the emergent chemical methods, we will seek to understand (and ultimately predict) how oxetane introduction affects the structure, dynamics, physicochemical properties and biology of peptides. Our long-term vision is for this new peptide bond isostere to be successfully deployed by scientists around the globe in drug discovery programmes.