Solid Phase Peptide Synthesis (SPPS)

Solid Phase Peptide Synthesis

Solid Phase Peptide Synthesis (SPPS) was introduced in the 1960s by Robert Bruce Merrifield¹, to whom was later awarded to Nobel Prize in Chemistry for this invention that revolutionized the field. In SPPS the C-terminus of the peptide chain is attached to a solid support and the peptide is grown in reversed order by adding amino acids to the N-terminus of the peptide. This allows for easy washing between each addition to the chain. Standard SPPS uses opposing pH-liability for the protections group of the side-chains and the N-terminus which reduces the risks of side-reactions.² In the CTB lab we have a large library of varied Fmoc-protected amino acids at our disposal when producing peptides and peptidomimetics. We commonly use Rink amide linker on a TentaGel bead during synthesis of peptides and peptidomimetics foreseen for solution based assays. CTB uses a number of other bead linkers including the groups new generation of an acid-labile safety-catch linker (SCAL2) developed in-house³. Safety catch linkers are needed for screening peptide and peptidomimetic libraries where they are produced, directly on bead, (called on-bead screening).

For more details on-bead based screening techniques and inhibitors for difficult targets, check the groups publication list on this website.

The scheme below outlines the general SPPS synthetic strategy used in the CTB lab.

1. Merrifield, R. B. Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. Journal of the American Chemical Society 85, 2149–2154 (1963).

2. Muriel, A., Jean, A. F., Jean, M. & Gilles, S. Methods and Protocols of Modern solid phase peptide synthesis. Molecular Biotechnology 33, (2006).

3. Portal, C. et al. Facile Synthesis of a Next Generation Safety-Catch Acid-Labile Linker, SCAL-2, Suitable for Solid-Phase Synthesis, On-Support Display and for Post-Synthesis Tagging. ChemistrySelect 2, 6658–6662 (2017).

CTB-MorPH

Conceptually, this software package allows a semi-automatic development of a peptidimimetic from a peptide. The necessary input is peptide sequence and structure of a protein-peptide or protein-protein interaction. Natural peptides are very important chemical tools for target validation, and might even represent potential drug candidates, however, it is often not easy to develop a natural peptide with the necessary high affinity and stability, while specificity is often achieved. The complete set of worldwide commercially available non-natural amino acids, amino-carboxylic acids and di-acids and amines are the input information for the position specific replacement of natural amino acids.