(281a) Convergent Synthesis of Peptides at Large Scale

Authors: 
Tandogan, N., Eli Lilly and Company
Seibert, K., Eli Lilly and Company
Kallman, N., Eli Lilly and Company
Groh, J. M., Eli Lilly and Company
Vaidyaraman, S., Eli Lilly and Company
Kopach, M., Eli Lilly and Company
Solid Phase Peptide Synthesis (SPPS) is the primary approach used in manufacturing to produce synthetic peptides. SPPS provides certain advantages over full solution phase chemistry approaches as the peptide on resin can be synthesized more rapidly and isolated with a higher purity. However, as a peptide chain grows longer the cost of SPPS increases disproportionately due to the use of excess reagents, the large volume of solvents, and decreasing coupling efficiency related to mass transfer resistances and steric hindrance.

Convergent peptide synthesis can be a very effective alternative to SPPS alone, when synthesizing long synthetic peptides. The method combines SPPS and the solution phase chemistry, where the fragments of a peptide chain are first synthesized linearly on resin, and then coupled in solution. The synthesis of short peptide fragments reduces the risk of single deletion impurities in the synthesis. Coupling fragments in solution also may significantly reduce the solvent use, resulting in greener synthetic approaches. Additionally, convergent approaches to peptide synthesis are far more amenable to alternative reactor designs such as flow infrastructure given the low concentration, high potency and high value of the peptide assets.

Control strategies for convergent chemistry approaches can also be significantly simplified given that peptides are routinely terminally purified through chromatographic means. Synthesis impurities that are markedly different in molecular weight are often more effectively separated in preparative chromatographic systems due to the differences in retention time. Synthesis impurities resulting from full linear builds are often characterized by single deletion impurities, with very similar amino acid sequence and therefore much more challenging to separate without sacrificing significant yield.

The focus of this presentation will be on our efforts to develop a platform for peptide synthesis focused on linear fragment builds, convergent fragment couplings, and enhanced process intensification and efficiency through incorporation of continuous processing strategies.