Roche (Basel, Switzerland) announced last week that it signed a drug-development deal worth up to $1.1 billion with the biopharmaceutical company Aileron Therapeutics (Cambridge, MA) to discover, develop, and commercialize “stapled peptides,” or drug candidates that use peptide-stabilization technology to enhance potency and cell permeability. So are stapled peptides a potential magic bullet in biopharmaceutical development?

Roche seems to think there is promise in the technology. Under its agreement, Roche will guarantee at least $25 million in funding for technology access fees and research and development to Aileron, which is eligible to receive up to $1.1 billion in payments based on discovery, development, regulatory, and commercialization milestones, if drug candidates are developed for five undisclosed drug targets in the following areas: oncology, virology, inflammation, metabolism, and central nervous system.

Aileron’s “stapled peptides” are designed 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). These limitations of small molecules and existing biologics make a vast array of potential drug targets “undruggable.” Approximately 80% of potential drug targets are considered “undruggable” by either modality (1, 2).

So how can these limitations be addressed? The concept of using peptides to modulate intracellular processes is not new, but these strategies have historically failed because peptides lack the ability to enter cells, are inherently unstable within the body, are rapidly broken down into inactive fragments by circulating enzymes such as proteases, and are quickly filtered from the bloodstream by the kidneys. Stapled peptides seek to resolve those problems. Because many “undruggable” therapeutic targets include those protein–protein interactions in which α-helices are required in lock-and-key-type mechanisms, an approach is to design α-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). Aileron stabilizes peptides by “stapling” them with hydrocarbon bonds into an α-helix. Once constrained in the α-helix structure, the peptides are protected from degradation by proteases. The stabilized α-helical peptides can penetrate cells by energy-dependent active transport and typically have a higher affinity to large protein surfaces (1, 2).

In advancing stapled peptides, Aileron has brought together scientific and financial weight. Aileron was cofounded in 2005 by Gregory L. Verdine, current chair of Aileron’s scientific advisory board and a chemical biologist at Harvard University, with initial funding from a private investment group. In 2006, the company acquired exclusive rights from Harvard University and the Dana-Farber Cancer Institute to develop and commercialize a drug-discovery pipeline of stapled peptides. In 2006/2007, Aileron licensed rights from the fine-chemicals and technology firm Materia (Pasadena, CA) for catalysts used in olefin metathesis. Materia holds the rights to the olefin metathesis technology developed by Robert H. Grubbs, professor at the California Institute of Technology, who was awarded the Nobel Prize in Chemistry in 2005 with Richard R. Schrock and Yves Chauvin for their work in olefin metathesis using ruthenium-based catalysts. Part of the reaction scope of olefin metathesis is ring-closing metathesis (RCM), which transforms a diene into a cyclic alkene and is used to create macrocycles, including bioactive cyclic peptidomimetics. Grubbs was one of the first to offer research describing RCM to tether residues of helical peptides (3, 4). In 2008, Aileron acquired exclusive rights from New York University for additional methods to stabilize peptides and peptidomimetics. In 2009, Aileron received $40 million in venture capital funding, which included funding from four pharmaceutical venture capital funds: SR One (GlaxoSmithKline’s venture capital fund), the Novartis Venture Fund, Lilly Ventures (Eli Lilly’s venture capital fund), and Roche Venture Fund.

So with a sound scientific basis and financial support from the pharmaceutical majors, it will be interesting to see how stapled-peptides fare. Like their “cousins,” aptamers and peptidomimetics, it has yet to be seen if “the offspring” of the marriage of small-molecules and biologics-based approaches can find a place at the drug-development table.

References
1. T. Sawyer, Chem. Biol. Drug. Des. 73 (1), 3–6 (2009).
2. W. Wolfson, Chem. & Biol. 16 (9), 910–911 (2009).
3. J.B. Binder and R. Raines, Curr. Opin. Chem. Biol. 12 (6), 767–773 (2008).
4. R. Grubbs, Angew. Chem. Int. Ed. 37, 3281–3284 (1998).