Stapled peptides advance
Scientists are advancing research in stapled peptides in both drug design and peptide synthesis. Researchers at the New
York Structural Biology Center reported on high-resolution nuclear magnetic resonance techniques with dynamic light-scattering
to characterize a family of hydrocarbon-stapled peptides with known inhibitory activity against the HIV-1 capsid assembly
to evaluate the various factors that modulate activity (1, 6). The researchers reported that helical peptides share a common
binding motif but differ in charge, the length and position of the staple. The research showed that the peptides share a propensity
to self-associate into organised polymeric structures mediated predominantly by hydrophobic interactions between the olefinic
chain and the aromatic side-chains from the peptide. The researchers also detailed the structural significance of the length
and position of the staple and of the olefinic bond isomerization in stabilizing the helical conformation of the peptides
as potential factors influencing polymerisation (1, 6).
Researchers at the Dana–Farber Cancer Institute, Children's Hospital in Boston, and Harvard University reported the use of
hydrocarbon double-stapling to remedy the proteolytic instability of a lengthy peptide (5, 7). Specifically, the researchers
applied the stapled approach to Fuzeon (enfuvirtide), a 36-amino-acid peptide that inhibits human immunodeficiency virus Type
1 (HIV-1) infection by targeting the viral fusion apparatus (5, 7).
The researchers noted that enfuvirtide is used as a salvage treatment option because of poor in vivo stability and poor oral bioavailability. To address the proteolytic shortcomings of long peptides as therapeutics, the researchers
studied the biophysical, biological and pharmacological impact of inserting all-hydrocarbon staples into the drug (5, 7).
The researchers found that the peptide double-stapling created protease resistance and improved pharmacokinetic properties,
including oral absorption. The hydrocarbon staples created a "proteolytic shield" by reinforcing the overall alpha-helical
structure, which slowed the kinetics of proteolysis and also created a complete blockade of peptide cleavage at the constrained
sites in the immediate vicinity of the staple (5, 7). The researchers noted the potential of double-stapling to other lengthy
But for all their promise, some researchers point to limited benefits of stapled peptides. Earlier this year, researchers
from the Walter and Eliza Hall Institute of Medical Research in Australia, the University of Melbourne and Roche's Genentech
reported on a study involving stapled peptides, specifically for stabilized BimBH3 peptides (BimSAHB), which had reduced affinity
for their targets, the pro-survival Bcl-2 proteins (8, 9). The researchers attributed the loss in affinity to disruption of
a network of stabilizing intramolecular interactions present in the bound state of the native peptide. They suggested that
altering the network may compromise binding affinity, as in the case of the BimBH3 stapled peptide in their study. They also
said that cells exposed to these peptides do not readily undergo apoptosis, which indicates that BimSAHB is not inherently
cell permeable (8, 9).
Patricia Van Arnum is a executive editor of Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org
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3. W. Wolfson, Chem. & Biol. 16 (9) 910–911 (2009).
4. Peptide Therapeutics Foundation, Development Trends for Peptide Therapeutics Report (San Diego, 2010).
5. P. Van Arnum, Pharm. Technol. 35 (5) 56-60 (2011).
6. S. Bhattacharya et al., Biopolymers 97 (5), 253-264 (2012).
7. G.H. Bird et al., Proc. Natl. Acad. Sci. USA, DOI/10.1073pnas.1002713107 (18 June 2010).
8. C. Drahl, Chem.& Eng. News 91 (5) 26-28 (2013)
9. T. Okamoto et al., ACS Chem. Biol. 8 (2) 297-302 (2013).