mRNA Display-based Discovery of Cyclic Peptide Supercatalysts Bearing Non-canonical Amino Acids

• Applicant: Tim Moritz Weber
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 582299334

Organocatalysis represents a central area of modern synthetic chemistry, as it enables the use of small, predominantly metal-free molecules to accelerate chemical transformations and thereby contributes to sustainable and environmentally compatible synthesis strategies. Despite significant progress, organocatalysis has so far relied mainly on small, typically amine-based molecules or linear peptides, and evolvable, genetically encodable catalyst systems are currently not available. In addition, the chemical functionality of the 20 canonical amino acids is inherently limited, which restricts the development of new catalytic motifs. The aim of this project is therefore to develop a novel mRNA-display platform that enables, for the first time, the selection-based identification of evolvable, catalytically active macrocyclic peptides. Furthermore, the approach will make targeted use of genetic code expansion to extend the restricted functional space of natural amino acids by introducing new catalytically relevant groups. Despite the broad applicability of mRNA display in ligand and inhibitor discovery, no existing system captures catalytic activity or enables the evolutionary optimisation of peptide catalysts. The project thus addresses a fundamental methodological gap at the interface of organocatalysis and display technologies. The project will establish a selection principle that links catalytic activity in a nitro-Michael addition directly to a sequence-specific detection signal. This will enable the systematic enrichment of catalytically active peptides and their corresponding genetic information in the form of mRNA from large sequence libraries. The combination of macrocyclisation, in vitro-generated peptide libraries, and targeted genetic code expansion has not previously been integrated into any platform designed for catalytic discovery. By combining modern in vitro evolution strategies with organocatalytically relevant reaction models, the project aims to elucidate the conditions under which catalytic activity can emerge from short peptide scaffolds. At the same time, it will establish a methodological foundation that enables mRNA display to be used, for the first time, as a tool for developing environmentally compatible peptide catalysts. In doing so, the project provides a conceptual advancement beyond conventional ligand-focused display systems and opens new perspectives for evolution-based organocatalyst discovery.

• DFG Programme: Fellowship
• International Connection: Netherlands
• Host: Dr. Ivana Drienovska