Bio-orthogonal metal catalysis: For selective modification of dehydroalanine in proteins and peptides

Nature makes beautiful molecules. Many of these molecules possess interesting properties which we can use in medicine. However, very often these natural products cannot find application as medicines directly, as properties like stability or solubility are not optimal for clinical use. One way to improve these properties, is by selective modification of these molecules. However, this is easier said than done. Many natural products are highly complex, which makes it difficult to make these molecules in the lab. It would be more efficient if bacteria can produce the complex molecules and then apply a late stage chemical modification to improve the properties of these complex molecules.

In this thesis different methods are described to modify complex peptides, made by bacteria, by means of metal catalysts. The catalyst were based on the metals palladium, rhodium, and iridium. The developed catalysts possess a very specific reactivity, so that the peptides only get modified at very specific positions. The new methods were developed to be applied under ‘bacterial-friendely’ conditions, so in water, pH 7 en maximum 37 oC. In this way, the chemical modification can be applied while bacteria produce the molecules. When the natural synthesis is complemented with unnatural chemistry, we can produce new molecules together which have improved properties. The start of a collaboration between chemists and nature towards the development of new medicines and antibiotics.