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Jul 1, 2010 (Vol. 30, No. 13)

New Practices Simplify Peptide Synthesis

Burgeoning Demand Makes Rapid and Economical Production Strategies Essential

  • Chemical Ligation

    Purity and reproducibility for pharmaceutical manufacture is a major challenge in peptide synthesis, according to Jeffrey Bode, Ph.D., associate professor at the University of Pennsylvania. To deal with these complex problems, he has developed a new reaction for amide formation in which two unprotected peptides, of virtually any sequence, can be ligated together to build up long peptides of high purity.

    “Ketoacid-hydroxylamine amide formation, can be employed as a general method for peptide ligation.”

    Dr. Bode noted that peptide targets include large 4,000–8,000 molecular weight therapeutic peptides, foldamers, and cyclic and hydrophobic peptides. A cogent example is the therapeutic peptide Fuzeon (Roche), which currently requires 106 chemical steps to synthesize, generates a massive quantity of waste byproduct, and can run up a bill of $20,000 per patient year.

    Chemical ligation, on the other hand, has the potential to shorten the process and avoid the formation of difficult to remove side products commonly formed in chemical peptide synthesis. To achieve this result, the team developed a new reaction for peptide bond formation, specifically the combination of an alpha-ketoacid and a hydroxylamine ligation.

    This unusual reaction makes possible peptide fragment couplings that do not need reagents or catalysts, do not generate byproducts, perform with multiple substrates, and can handle the unprotected functional groups found on peptide side chains.

    At this time the most significant challenge in the application of the process is the development of a practical synthetic method for C-terminal peptide ketoacids and N-terminal hydroxylamines, Dr. Bode explained. A pivotal step in this strategy is the development of a chemoselective conversion of cyanosulfurylides to alpha-ketoacids and the implementation of solid-phase synthesis of N-terminal hydroxylamines. Using this approach, a high purity final product can be obtained with chemistry that should be amenable to upscaling to kilogram amounts.

    Looking forward, Dr. Bode feels that the technology of peptide synthesis by ligation can fill a significant gap in the production of therapeutic molecules. “For large proteins, cloning and genetic engineering is still the way to go,” he stated, but for molecules in the range of 30 to 50 amino acids, peptide synthesis is faster and more cost effective.”

    This may not be the first option that directors of biotechnology programs would favor, but given the dramatic advances reported at these conferences, it may be the most efficacious.

    A presentation at Cambridge Chemistry’s “Peptide Conference” highlighted a new approach to the design of solid supports for peptide synthesis, concentrating on the industrial-scale production of peptides.

    Don Wellings, Ph.D., CEO of SpheriTech, outlined his company’s technology for the manufacturing of solid supports for peptide synthesis. The concept of a polymer support contained within a column was put together in the 1980s as a means of minimizing solvent usage in a closed system that lends itself to automation.

    “Our polymer-encapsulation technology employs hollow glass beads, low cost and of high quality, they favor encapsulation of any polymer.”

    Dr. Wellings has developed a technology based on an idea that complements continuous flow in peptide synthesis. “Imagine if the polymer particles floated; you could do solid-phase synthesis in a standard solution-phase reactor or even a separating funnel, no filter plate, no sinter, no porous disc.

    Preformed hollow glass microspheres form a seed for preparation of polymer particles at a low cost per cubic meter of glass beads. From a theoretical point of view, virtually any polymer, such as polydimethyl acrylamide and polystyrene, can be coated on the outside of a hollow sphere. The advantage here lies not only in the hollow glass seed but in the ease of handling a buoyant polymeric particle.

    Peptide synthetic chemistry is not a new endeavor, but it has undergone dramatic changes in recent years. As new peptides are discovered the demand for their production in bulk grows stronger. The improvements and optimizations in solid-phase peptide synthesis mean that the use of large quantities of noxious organic reagents can be avoided. This means a more environmentally friendly and economical means of production of peptides is now practical and readily available.


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