Jonathan R. Heal

Yeast Synthetic Biology Platform Generates Novel Chemical Structures as Scaffolds for Drug Discovery

Synthetic biology has been heralded as a new bioengineering platform for the production of bulk and specialty chemicals, drugs, and fuels. Here, we report for the first time a series of 74 novel compounds produced using a combinatorial genetics approach in baker’s yeast. Based on the concept of “coevolution” with target proteins in an intracellular primary survival assay, the identified, mostly scaffold-sized (200–350 MW) compounds, which displayed excellent biological activity, can be considered as prevalidated hits. Of the molecules found, >75% have not been described previously; 20% of the compounds exhibit novel scaffolds. Their structural and physicochemical properties comply with established rules of drug- and fragment-likeness and exhibit increased structural complexities compared to synthetically produced fragments. In summary, the synthetic biology approach described here represents a completely new, complementary strategy for hit and early lead identification that can be easily integrated into the existing drug discovery process.

Inhibition of β‐Amyloid Aggregation and Neurotoxicity by Complementary (Antisense) Peptides

Complementary peptides are coded for by the nucleotide sequence (read 5′→3′) of the complementary strand of DNA. By reading the sequence of complementary DNA in the 3′→5′ direction, alternative complementary peptides may be derived. We describe the derivation, testing and analysis of six complementary peptides designed against β‐amyloid peptide 1‐40 (Aβ1‐40). Data is presented to show that one peptide, designated 3′→5′ βCP1‐15, binds specifically to Aβ1‐40, and inhibits both fibrilisation and neurotoxicity in vitro. This suggests that complementary peptides could be useful leads for drug discovery, especially where diseases of protein misfolding are concerned.