We are active in the field of Chemical Biology, and our research centers around the synthesis of peptide-derived molecules and the engineering of proteins using organic chemistry. Central aspects are the synthesis of non-natural amino acids as well as modified peptides, and the use of biocompatible reactions for the selective functionalization of unprotected peptides and proteins. We use these techniques e.g. for the development of novel bioactive peptidomimetics and for chemical protein engineering.

Proteomimetics & Chemical protein engineering

Proteins have evolved as a variable platform that provides access to molecules with diverse shapes, sizes and functions. These features have inspired chemists for decades to seek artificial mimetics of proteins with improved or novel properties (perspective: Horne & Grossmann, 2020, Nature Chem.). Along those lines, we pursue the design and synthesis of stabilized protein fragments. We have also developed the INCYPRO technology (In situ Cyclization of Proteins) which facilitates a structure-based design process towards proteins with increased tolerance towards thermal and chemical stress. INCYPRO involves the introduction of three surface-exposed cysteines into the enzyme which are subsequently reacted with a triselectrophilc crosslinker. We have designed a library of crosslinkers allowing the fine-tuning of protein or enzyme properties.

selected publications:
GH Hutchins et al., Chem. 10, 615–627 (2024) 
M Wendt et al., Angew. Chem. Int. Ed. 60, 13937–13944 (2021)
H Adihou et al., Nature Commun. 11, 5425 (2020)
WS Horne & TN Grossmann, Nature Chem. 12, 331–337 (2020) – review
S Neubacher et al., J. Org. Chem. 85, 1476–1483 (2020)
M Pelay‑Gimeno et al., Angew. Chem. Int. Ed. 57, 11164–11170 (2018)

Peptidomimetics & Non-natural amino acids

Ligands that selectively bind to biomolecular targets are a prerequisite for most strategies aiming at the elucidation or modulation of biological processes. The discovery of these ligands can be very challenging. Giving the large amount of available structural data, peptide binding epitopes provide a rich source of inspiration for novel ligands. Preorganization of such epitopes into their bioactive conformation or the use of rigid organic scaffolds provide so-called peptidomimetics (Class A – D, see schematic overview (JPEG) below, M Pelay‑Gimeno et al.) with increased binding affinity and/or bioavailability. We develop strategies that allow the design of novel Class A and B peptidomimetics (examples are shown below).

selected publications:
N McLoughlin et al., Angew. Chem. Int. Ed. 62, e202308028 (2023)
A Kuepper et al., Nucleic Acids Res. 49, 12622–12633 (2021)
K Wallraven et al., Chem. Sci. 11, 2269–2276 (2020)
S Jeganathan et al., Angew. Chem. Int. Ed. 58, 17351–17358 (2019)
L Dietrich et al., Cell Chem. Biol. 24, 958–968 (2017)
PM Cromm et al., Nature Commun. 7, 11300 (2016)
M Pelay‑Gimeno et al., Angew. Chem. Int. Ed. 54, 8896–8927 (2015) – review

Biocompatible reactions for protein modification

The selective chemical modification of proteins is a challenging task with important implications for the development of therapeutic biologics and for biotechnological applications. We explore the potential of biocompatible reactions for the functionalization of native proteins entirely composed of natural amino acids. Biocompatible reactions (in contrast to bioorthogonal chemistry) target proteinogenic amino acids and are tuned to exhibit selectivity for particular amino acids on the protein surface. We pursue two different routes to achieve selectivity enhancements: The use of proximity-induced reactions in which a ligand directs the reactive group towards a particular amino acid (either template-controlled or ligand-directed), and via the identification of electrophilic groups which show high sensitivity towards the amino acid micro-environment (e.g. used for protein macrocylizations).

selected publications:
F Paulussen et al., J. Am. Chem. Soc. 144, 15303–15313 (2022) 
S Neubacher et al., J. Org. Chem. 85, 1476–1483 (2020)
C Mueller et al., Angew. Chem. Int. Ed. 57, 17079–17083 (2018)
M Pelay‑Gimeno et al., Angew. Chem. Int. Ed., 57, 11164–11170 (2018)
C Stiller et al., ACS Chem. Biol. 12, 504–509 (2017)
CU Lee et al., Angew. Chem. Int. Ed. 54, 13796–13800 (2015)
N Brauckhoff et al., Angew. Chem. Int. Ed. 53, 4337–4340 (2014)

Techniques & Instrumentation

Chemical synthesis
Solid-phase peptide synthesis
Protein expression & Purification
Peptide & Protein characterization
Fluorescence microscopy
Protein crystallography