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An original biotechnological approach to create new bioactive molecules


​Muriel Gondry's Research Team (I2BC @ Saclay / SBIGeM), in collaboration with SIMOPRO and Biomolecules Laboratory of the Sorbonne University's one, produced 200 cyclodipeptides containing non-natural amino acids by luring and diverting the cellular machinery for the synthesis of proteins. This unprecedented approach significantly increases the diversity of these bioactive molecules.

Published on 5 March 2018

Abstract

The manipulation of natural product biosynthetic pathways is a powerful means of expanding the chemical diversity of bioactive molecules. 2,5-diketopiperazines (2,5-DKPs) have been widely developed by medicinal chemists, but their biological production is yet to be exploited. We introduce an in vivo method for incorporating non-canonical amino acids (ncAAs) into 2,5-DKPs using cyclodipeptide synthases (CDPSs), the enzymes responsible for scaffold assembly in many 2,5-DKP biosynthetic pathways. CDPSs use aminoacyl-tRNAs as substrates. We exploited the natural ability of aminoacyl-tRNA synthetases to load ncAAs onto tRNAs. We found 26 ncAAs to be usable as substrates by CDPSs, leading to the enzymatic production of approximately 200 non-canonical cyclodipeptides. CDPSs constitute an efficient enzymatic tool for the synthesis of highly diverse 2,5-DKPs. Such diversity could be further expanded, for example, by using various cyclodipeptide-tailoring enzymes found in 2,5-DKP biosynthetic pathways.

Read the French version.

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