Oligos&Peptide_2016 - page 23

Monographic special issue:
Oligos & Peptides -
Chimica Oggi - Chemistry Today
- vol. 34(2) March/April 2016
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.
Highlights on recent peptide achievements
KEYWORDS: Peptide therapeutics, cell-penetrating peptides, stapled
peptides, drug delivery, scale-up peptide manufacturing.
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.
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.
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 intact peptide
species. Additionally, some structural information about peptides
can be obtained by peptide fragmentation within the instrument.
Mass spec is commonly coupled with other analytical techniques
like liquid chromatography (LC-MS). More recently, mass spec has
been coupled with amino acid analysis (AAA-MS) to provide a
sensitive analytical method for peptide quantitation.
Traditionally peptides have engaged extracellular targets; however,
getting peptides into the cell expands the number of potential
targets for therapeutic intervention. Cell-penetrating peptides
Executive Director, Applied Translational Medicine, Celerion, Inc., USA
Bruce H. Morimoto
Dearest Readers,
for the 2016 Special Issue on Oligos & Peptides, we asked two experts – Bruce Morimoto from Celerion, and Kathryn Ackley from Nitto
Denko Avecia – to write overview papers on the state of the art on peptides and oligos respectively, starting from inputs coming from
companies focused on these sectors. These enterprises where asked to write brief articles on their view on the most outstanding
peptides/oligonucleotides achievement in the past couple of years, from breakthroughs in manufacturing to new applications for
peptides/oligonucleotides, taking in consideration clinical aspects and manufacturing and CMC aspects.
So far, our Special Issue presents peptides and oligos in two different sections, starting with the overview article and going through each
company paper.
We hope you will find it interesting and useful and look forward to receive your feedback to our email address
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