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p. 21-22 / OVERVIEW ON PEPTIDES
AN INTRODUCTION:
Highlights on recent peptide achievements

BRUCE H. MORIMOTO
Executive Director, Applied Translational Medicine, Celerion, Inc., USA

ABSTRACT: Over 115 years have passed since Emil Fischer synthesized glycylglycine, a dipeptide (1), and it has been more than 50 years since Bruce Merrifield’s Nobel Prize winning paper was published on solid-phase synthesis of peptides (2). Progress in developing peptide therapeutics requires continuous innovation in multiple areas, including basic research discoveries, development of novel chemistries, and improvements in manufacturing. This issue contains articles on the recent achievements in peptides through the eyes of several industry leaders.
KEYWORDS: Peptide therapeutics, cell-penetrating peptides, stapled peptides, drug delivery, scale-up peptide manufacturing.


BIGGER AND MORE
Solid-phase synthesis revolutionized peptide chemistry and allowed for longer peptides to be made (3).  However, to make more complex and biologically active molecules, ligation chemistry enabled peptides to be linked together.   In this issue, Dr Michael Pennington, Peptides International and Daniel Bourgin from Dr Reddy’s write about the need to develop and refine new chemistries to synthesize longer and more complex peptides.  Chemical ligation and “click-chemistry” are some of the methods to join shorter synthetic fragments. 
Large scale, commercial peptide synthesis emerged nearly 20 years ago with enfuvirtide also known as Fuzeon™ as explained by Dr Gary Erickson from CBL Biopharma.  This required improvements in scale-up which included a significant chemical engineering effort in developing uniform mixing, rapid transfer of intermediates and solvents, and the optimization of producing the amino acid building blocks (fmoc-amino acids).
In addition to making more peptide, it is critical to develop manufacturing processes that are robust, reproducible and cost-effective. Anders Tsirk and Jon Rasmussen from PolyPeptide Group describe how Quality-by-Design (QbD) can be used to improve yield, throughput and quality in the manufacturing of peptide therapeutics.

DON’T LEAVE ME NOW: STRUCTURE AND STABILITY
Stapled peptides is a topic highlighted by both Dr Pennington from Peptides International and Dr Bennett from AAPPTec, LLC.  Stapled peptides are constrained by the formation of covalent, intramolecular bonds which creates helical peptide structures.  There are several examples of stapled peptides as therapeutics, like the HIV-1 integrase inhibitor and the dual MDM2/MDMX inhibitor.  Several companies are developing cyclic or conformation-restricted therapeutic peptides.
Peptides are susceptible to degradation by proteolysis or excretion by the kidney.  This often limits the circulation time in the body.  Daniel Bourgin describes how PEGylation can increase a peptide’s circulating plasma half-life by protecting it from proteases and also reducing excretion in the kidney. 

WHAT DO WE HAVE?
Once a peptide is made, it is critical not only to identify its structure but also to characterize it.  This requires direct analytical techniques.  One recent area, as described by Dr Mainfroid from Eurogentec SA, is the application of mass spectrometry.  High resolution mass spec allows for quantitation of the...
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