Mike Pennington, Ph.D.
will be participating as a speaker in this live virtual conference hosted by tks. Visit the website below to register.
Large scale production of complex disulfide peptides
Peptides without some type of stabilizing element exist as an equilibrium between multiple conformational states. One of the principal means of stabilizing peptides in nature has been different cyclization motifs. The most common of these motifs is the disulfide bond. Synthesis methods for peptides containing Cysteine have improved allowing for minimal racemization of this sometimes-troublesome residue. Peptides with less than 60 residues with multiple disulfide bonds are often referred to as “disulfide-rich peptides” (DRP). Examples of these peptides which have entered into clinical development and ultimately to commercially approved drug products include: insulin (multiple analogs), ziconotide (ω-conotoxin), aprotinin (bovine pancreatic trypsin inhibitor), linaclotide (heat-stable enterotoxin, plecanatide (Glu4-uroguanylin). Numerous other DRPs are in clinical development. These include: dalazatide (ShK peptide analog), tozuleristide (dye-labeled chlorotoxin), hepcidin and α-conotoxin RgIA. Commercial manufacturing of these peptide API’s requires a combination of a robust synthetic production which may involve total SPPS or a combination of hybrid methods as well as an optimized folding procedure to generate the desired disulfide bonding pattern. Ambiopharm’s approach to manufacturing peptides containing Cys will be discussed as well as several case studies: eptifibatide (1 disulfide bond), plecanatide (2 disulfide bonds), linaclotide (three disulfide bonds) and chlorotoxin (4 disulfide bonds)) of DRPs will be provided.