Polypeptides are fascinating bio-based materials applicable to various fields because of their sequential variety which imparts a wide range of physical and physiological properties. Unlike conventional synthetic methods for polypeptides such as solid phase peptide synthesis and ring opening polymerization of amino acid <i>N</i>-carboxyanhydrides (NCAs), chemoenzymatic synthesis using proteases as a catalyst proceeds in more environmentally benign conditions. The chemoenzymatic polymerization of amino acid ester mediated by proteases possesses several synthetic advantages in terms of chemoselective synthesis of polypeptides with functional sequences. For example, amino acid monomers with a reactive group on their side chain can polymerize in the presence of proteases without any protecting group on the side chain. We successfully synthesized poly(serine) by papain-catalyzed polymerization of serine (Ser) ethyl ester without protecting the hydroxy group on the side chain. Another advantage is that periodic sequences are readily available via chemoenzymatic polymerization of oligopeptide monomers. In the protease-mediated polymerization, the affinity of monomers for proteases is a key to facilitate the sequence-specific aminolysis reactions to obtain polypeptides containing functional sequences. We attempted to carry out the polymerization of a series of histidine (His)-containing oligopeptide monomers using papain. His ethyl ester did not polymerize via papain-catalyzed polymerization because of low affinity of His residue for papain. In contrast, the combination of His with glycine (Gly) in HisGly dipeptide and GlyHisGly tripeptide monomers allowed these monomers to polymerize in the presence of papain, resulting in His-containing periodic polypeptides with a high degree of polymerization up to 40. However, GlyHis dipeptide monomer did not undergo the polymerization. This is probably due to the difference of affinity for papain between HisGly and GlyHis dipeptides.

Chemoselective synthesis of functional polypeptides mediated by enzymes

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