Approaches to peptide synthesis
Academic and industry collaboration in pharmaceutical sciences
|
Stapled peptides.
One important collaboration in peptide drug development is between the biopharmaceutical company Aileron Therapeutics
and Roche. In November 2011, Aileron expanded its collaboration with Roche for the discovery, development, and commercialization
of stapled-peptide drugs. The potential $1.1-billion drug-development collaboration, launched in August 2010, encompasses
up to five programs with the initial two programs focused on oncology and then a third program launched late last focused
on inflammatory diseases.
Stapled peptides use peptide-stabilization technology to enhance potency and cell permeability of a drug to address pharmacological
limitations of small molecules and existing biologics in intracellular protein–protein interactions. Although small molecules
are able to penetrate cells, the large binding surfaces for intracellular protein–protein interactions often make small-molecule
modulators ineffective. Although peptides and proteins have the size and functionality to effectively modulate intracellular
protein–protein interactions, they often do not permeate cells and therefore are used to modulate extracellular targets, such
as receptors (1, 10). Stapled peptides seek to resolve those problems. Because many undruggable therapeutic targets include
those protein–protein interactions in which alpha-helices are required in lock-and-key-type mechanisms, an approach is to
design alpha-helical peptides that have structural and functional properties that enable them to penetrate into the cell,
bind to the therapeutic target, and modulate the biological pathway (1, 10). Aileron stabilizes peptides by "stapling" them
with hydrocarbon bonds into an alpha-helix. Once constrained in the alpha-helix structure, the peptides are protected from
degradation by proteases. The stabilized alpha-helical peptides can penetrate cells by energy-dependent active transport and
typically have a higher affinity to large protein surfaces (1, 2, 10).
Researchers at the New York Structural Biology Center recently reported on high-resolution solution nuclear magnetic resonance
techniques with dynamic light-scattering to characterize a family of hydrocarbon-stapled peptides with known inhibitory activity
against HIV-1 capsid assembly to evaluate the various factors that modulate activity. 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 organized 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 olefinic bond isomerization in stabilizing the helical conformation
of the peptides as potential factors influencing polymerization (11).
|
