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Design of Helical Peptides: From Cys–Cys Stapling to New Cys–Lys Methodologies by François Pierrard -
Vendredi 5 juin 2026 à 16h00 - Auditoire 51B - Avenue Mounier, 51 - 1200 Bruxelles
Peptide stapling consists in covalently linking two amino acid side chains to restrict the conformational freedom of a peptide. Since this can increase the helical propensity of peptides, stapling represents a well-known approach for mimicking α-helical protein segments and designing potential inhibitors of protein–protein interactions.
A wide range of chemical methods has been described for the preparation of stapled peptides, using either natural or unnatural amino acids. Among these approaches, strategies involving two cysteines as anchoring residues (“Cys–Cys stapling”) are the most widely used, enabling the introduction of symmetrical linkers via stapling reagents carrying two identical thiol-reactive groups. In the first part of this project, various Cys–Cys cross-linking reagents were used to generate, from a single linear peptide, a library of i,i+4 stapled peptides targeting lactate dehydrogenase B, a tetrameric enzyme that plays a key role in the survival of cancer cells.
On the other hand, “Cys–Lys stapling” exploits the difference in nucleophilicity between thiol and amine side chains of cysteine and lysine residues, respectively. This approach enables the incorporation of non-symmetrical linkers, thereby expanding structural diversity. However, it remains underexplored to date, and novel chemically original methods are needed.
In the second part of this work, a new Cys–Lys stapling methodology was developed, based on sequential S-alkylation and intramolecular reductive amination. After optimization of the one-pot procedure, the scope of the method was evaluated through its application to various peptides—differing in amine side-chain length and in the presence or absence of potential competing nucleophiles—as well as to a range of stapling reagents varying in both the nature of the thiol-reactive group and the linker structure. Modulating the length of the amine side chain was shown to allow fine-tuning of the helicity of the resulting macrocyclic peptides. Moreover, since the reductive amination step yields a secondary amine that remains nucleophilic, further structural diversification was achieved through bicyclization and pos-stapling derivatization.
Jury Members :
Prof. Olivier Riant (UCLouvain) (Supervisor)
Prof. Raphaël Frédérick (UCLouvain) (Supervisor)
Prof. Jean-François Gohy (UCLouvain) (Chairperson)
Prof. Michael Singleton (UCLouvain) (Secretary)
Prof. Jérôme Waser (Ecole Polytechnique Fédérale de Lausanne)
Prof. Morgane Pasco (Université de Bordeaux)
Prof. Charlotte Martin (Vrije Universiteit Brussel)
Pay attention : the public defense of François Pierrard will also take place in the form of a videoconference
