Cole W. Seifert and Guigen Li
GAP Peptides LLC, Lubbock, TX 79415, United States; Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, United States; Institute of Chemistry and Biomedical Sciences, Nanjing University, Nanjing 210093, P. R. China.
The peptide therapeutics market has been growing rapidly for years, both financially and as an increasing sector of the pharmaceutical industry.1 This market is projected to continue growing; therefore, new synthetic methodologies to reduce the cost of peptide synthesis and enable larger scale syntheses are highly desired.2 We have developed a solution-phase, Fmoc / tBu peptide synthesis method utilizing Group-Assisted Purification (GAP) chemistry, by design of a small-molecule (MW = 292 Da) protecting group. This protecting group, equipped with a phosphine oxide moiety, facilitates selective precipitation of the peptide from solution after each coupling step, with an average isolated yield per coupling of 97%. All fully protected peptides are white, crystalline solids that are easy to handle and can be stored for over 1 year without noticeable degradation. Reactions are run in homogeneous solution without the use of bulky polymers, leading to highly efficient couplings and high crude peptide purity. GAP peptide synthesis is amenable to a wide variety of coupling strategies, protecting groups, and deprotection reagents. Our process is also semi-automated, and we are working towards full automation. Examples of peptides synthesized using the GAP process are presented.
1. Craik, D. J.; Fairlie, D. P.; Liras, S.; Price, D., The Future of Peptide-based Drugs. Chem. Biol. Drug Des. 2013, 81 (1), 136-147.
2. Fosgerau, K.; Hoffmann, T., Peptide therapeutics: current status and future directions. Drug Discov. Today 2015, 20 (1), 122-128.