Advancing Peptide Synthesis Through Stapled Peptides - Pharmaceutical Technology

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Advancing Peptide Synthesis Through Stapled Peptides
Stapled peptides offer promise to enable cell permeability, binding to therapeutic targets, and modulation of biological pathways.


Pharmaceutical Technology
Volume 37, Issue 8, pp. 48-50

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 peptide-based drugs.

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,

References
1. P. Van Arnum, Pharm. Technol. 36 (6) 42-43, 62 (2012).
2. T. Sawyer, Chem. Biol. Drug. Des. 73 (1) 3–6 (2009).
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).


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