Tony Holý Lecture – Morten Peter Meldal

The CuAAC click reaction¹ discovered in 2001 will be described, with mechanistic discussions and applications. The criteria for a click reaction will be outlined, and our INAIC click reaction will be presented. This reaction was discovered by NMR investigations of peptide aldehydes, which showed entropy-driven quantitative and highly selective reaction with backbone or sidechain amides in the peptide, to form reactive N-acyl iminium ions. These react with C, O, N or S nucleophiles in a tandem intramolecular reaction to form multiple heterocycles in a stereo- and enantioselective manner.² A range of 3D-ligands for GPCRs was produced and assayed in a special gene eGFP reporter assay.³ Cells were attached to beads and mixed with a combinatorial split/mix library of putative agonist ligands.⁴ Active ligands were identified. A small library of clicked, macrocyclic peptides was produced and screened for MC4R activation.⁵

1. Tornøe, C. W., & Meldal, M. Peptides: The Wave of the Future: Proceedings of the Second International and the Seventeenth American Peptide Symposium, June 9–14, 2001, San Diego, California, USA, 2001, 263-264.
2. Nielsen, T. E., & Meldal, M. The Journal of Organic Chemistry, 69(11), 2004, 3765-3773.
3. Hald, H., Wu, B., Bouakaz, L., & Meldal, M. Analytical biochemistry, 476, 2015, 40-44.
4. Meldal, M., Wu, B., Diness, F., Michael, R., & Hagel, G. ChemBioChem, 12(16), 2011, 2463-2470.
5. Palmer, D., Gonçalves, J. P., V. Hansen, L., Wu, B., Hald, H., Schoffelen, S., & Meldal, M. Journal of Medicinal Chemistry, 60(21), 2017, 8716-8730.