A Supramolecular Peptide Synthesizer

Abstract

The synthesis of peptides has been an active area of research for chemists for many decades. Hallmarks in this area include the first synthesis of a peptide in solution by Fischer and Fourneau in 1901, Merrifield s peptide synthesis on the solid support, and the development of ligation reactions, especially native chemical ligation (NCL) by Kent et al. , for the assembly of unprotected peptides and proteins of synthetic or biotechnological origin. Solid-phase peptide synthesis (SPPS) developed from these revolutionary concepts and has become the method of choice; the growing peptide is immobilized to an insoluble resin, and in this way the scalable synthesis of polypeptides with up to 40–50 amino acids can be achieved in high yields. SPPS follows a stepwise protocol to add amino acids one at a time to a growing peptide chain. Importantly, each amino acid building block has to be activated and orthogonally protected at its N-terminus and functional side chains. The selective removal of the N-terminal protecting group and subsequent coupling with the next amino acid in a synthetic protocol are steps that can easily be automated for the sequence-specific incorporation of both natural and unnatural amino acid building blocks. Despite many improvements in the area of SPPS the general concept is still valid: The synthesis proceeds—in contrast to peptide biosynthesis— from the C-terminus to the N-terminus and the specificity is ensured by the reaction of a selected activated amino acid building block with an N-terminally unprotected solidsupported peptide of choice. Very recently in early 2013, Leigh and co-workers reported a conceptually new approach to peptide synthesis, in which the amino acids are preorganized in a supramolecular architecture for the synthesis of small peptides. For reactions in this artificial molecular machine, close analogies can be drawn to natural ribosomal and nonribosomal peptide biosynthesis. This effort can be considered as a milestone in the design of biologically inspired supramolecular machines. The most interesting aspect of this work is not only the capability of the molecular machine to synthesize peptides but also how the design makes use of nature s approach: There are two biosynthetic pathways in nature for the assembly of amino acids to form polypeptides, which rely either on ribosomal peptide synthesis (RPS) or on nonribosomal peptide synthesis (NRPS). Ribosomal peptides are synthesized by translation of the messenger RNA (mRNA) (Scheme 1A), thereby taking advantage of several