Geno-Chemetics – a new paradigm in natural product analogue generation that we are developing (Combining Synthetic Biology and Synthetic Chemistry).

Chemically labile motifs within natural products can cause a problem for the synthetic chemist and lead to side reactions. Significant effort is employed to protect sensitive functionality or to avoid introducing this into the natural product until the final stage in the synthesis. Conversely, using synthetic biology to harness biosynthetic processes we will engineer chemically orthogonal and reactive functionality into natural products (the antithesis of protecting groups). Rather than employing a long chemical synthesis of a modified natural product core, the selectively activated core will be made by introducing foreign genes into the natural product generating microorganism to act in concert with the existing biosynthetic machinery. Expression of the foreign gene will result in the introduction of a reactive, chemically orthogonal handle into a selected site within the natural product. This reactive functional handle may then be subjected to a large portfolio of reactions enabling its selective modification.

Scheme 1. GenoChemetics: a new paradigm in natural product analogue synthesis. Gene expression enables selective chemical functionalization with the potential to open a multitude of horizons in natural product research, medicinal chemistry, and chemical biology