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Manufacturing and PEGylation of a Dual‐Acting Peptide for Diabetes
Author(s) -
Krüger Jochen,
Minuth Torsten,
Schröder Werner,
Werwath Jörn
Publication year - 2008
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200800722
Subject(s) - pegylation , chemistry , moiety , peptide , peptide synthesis , combinatorial chemistry , solid phase synthesis , yield (engineering) , molecule , stereochemistry , biochemistry , organic chemistry , materials science , polyethylene glycol , metallurgy
In the given manuscript we summarize our activities to develop a scalable synthesis for a PEGylated peptide, which undergoes development for metabolic disorders. The polypeptide contains a sequence of 31 natural amino acids and carries a site‐specific PEGylation at the C‐terminus. Initial synthetic studies revealed that the peptide moiety of the target molecule is not an ideal target for a linear solid‐phase process, as we were confronted with “difficult sequences”, which led to a low‐yielding process. Subsequently, we developed a mixed‐phase synthesis, which included production of fragments through solid‐phase peptide synthesis, followed by an assembly of these fragments in solution. We were able to show that this new process delivered the desired peptide moiety in gram‐scale with high purity. The overall yield was improved from 1 % for the sequential solid‐phase process to 9 % for the fragment synthesis. Finally, a PEGylation process was installed to deliver the drug substance for preclinical and clinical testing. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)