With the increasing focus on peptides as potential therapeutics, the need for fast and efficient methods for solid phase peptide synthesis has become paramount. Conventional peptide synthesis methods typically suffer from slow and incomplete reactions, especially when synthesizing long or difficult peptide sequences. During the course of conventional peptide synthesis, the growing peptide chain can form aggregates with itself or neighboring chains, producing low-quality peptides. This limitation has been overcome through the use of microwave irradiation. Due to its highly charged resonance structure, the peptide bond will readily absorb microwave energy, inducing molecular motion within the peptide. This random motion can overcome chain aggregation within the peptide, resulting in a significant increases in the peptide purity.
The Liberty Microwave Peptide Synthesizer from CEM automates the peptide synthesis process utilizing microwave energy to accelerate both the coupling and deprotection reactions. In addition to overcoming chain aggregation, microwave irradiation can considerably increase the speed at which peptides are synthesized. Microwave energy allows the amino acid coupling to be completed in 5 minutes instead of 2 hours. The Fmoc deprotection reaction can also be accelerated in the microwave, decreasing the reaction time from at least 15 minutes to only three.
Microwave energy has been applied to the synthesis of a variety of different types of peptides including difficult to synthesize peptides such as ?-amyloid, cyclic peptides, glycopeptides, peptide dendrimers and polymers, and peptidomimetics such as ?-peptides and peptoids. A recent development is in the synthesis of peptide nucleic acid (PNA) polyamides. A method was developed to synthesize PNA oligomers using microwave irradiation to accelerate the synthesis as well as increase the yield and purity. Microwave irradiation has also been used to accelerate the synthesis of peptides containing sterically hindered amino acids—including N-methyl rich peptides—from 2 to 4 hours to only 20 minutes.1 The coupling of these highly sterically hindered residues typically suffers from low yield and requires expensive coupling reagents. A direct comparison to conventional synthesis conditions at the exact same time and temperature provided the peptides in very low purity.
1. Rodríguez H, Suarez M, Albericio F. A convenient microwave-enhanced solid-phase synthesis of short chain N-methyl-rich peptides. J Pept Sci. 2010;16:136-140.