Towards the Chemical Synthesis of Proteins

Abstract

The chemical total synthesis of proteins using solid supports has made great progress. It is therefore becoming a reality what E. Fischer already predicted in 1902: “I foresee the time when physiological chemistry… is able to prepare synthetic enzymes.” The synthesis of peptides of up to 20 amino acids by the well‐established solid‐phase procedure on polymeric supports (SPPS) has made great progress through the development of newer supports. At the same time, methods have emerged which facilitate the separation and characterization of peptides, thus allowing optimization of the synthesis of pure materials. The new supports which enable one to synthesize peptides by a rapid continuous flow procedure are characterized by hydrophilicity, beads of approximately equal size, similar swelling properties in the solvents used for peptide synthesis, and stability at high pressure. With graft copolymers of weakly cross‐linked polystyrene and linear polyethylene glycol (PEG), the synthetic cycle for coupling of one amino acid can routinely be reduced to 10–20 min with a concomitant higher yield. With beads of monodispersed graft copolymer of 10 μm diameter, a synthetic cycle can, in principle, be shortened to 1–5 min. By utilizing this high‐speed solid‐phase procedure, larger peptides up to the size of proteins could also be prepared in a few hours. With newer mass spectroscopic methods such as ion‐spray mass spectrometry, peptides of up to a molecular mass of 100 kDa can be characterized, and with the advent of capillary electrophoresis, another very efficient separation tool, besides HPLC, is at our disposal.