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

A commercial path for stapled peptides
Aileron Therapeutics is one company specializing in developing stapled peptides. Its technology 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 (1–3, 5).

Aileron was cofounded in 2005 by Gregory L. Verdine, recently named CEO of the genomics company Warp Drive Bio. Verfine, who served as professor of chemistry at Harvard University, director of the Harvard/Dana–Farber Programme in Cancer Chemical Biology, and executive director of the Chemical Biology Initiative at the Dana–Farber Cancer Institute, is noted for advancing the field of stapled peptides. In 2006, Aileron acquired exclusive rights from Harvard University in Massachusetts 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 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 (1, 5).

Aileron is partnered with Roche for stapled peptides. The companies formed a potential $1.1-billion drug-development collaboration in 2010 for the discovery, development, and commercialization of stapled-peptide drugs and later expanded the collaboration. The initial program encompasses up to five programs with the initial two programs targeting oncology, and the third program, launched in late 2011, involving inflammatory diseases. Aileron also is partnered with Novartis and Eli Lilly through the respective venture funds of those companies (1, 5). In May 2013, Aileron announced the completion of the first-in-human study of its lead stapled peptide drug, ALRN-5281, a proprietary, long-acting growth-hormone-releasing hormone agonist for treating orphan endocrine disorders.

Other companies are involved in stapled peptides. In November 2012, MorphoSys, a company specializing in antibody technology, partnered with the Dutch biopharmaceutical company Lanthio Pharma, which is involved with discovering and developing lantipeptides, a class of stapled peptides with high target selectivity and improved drug-like properties, which the company produces through its proprietary technology LanthioPep. The technology is used to identify peptides that are selective for a specific disease target and to stabilize them in their optimal structural conformation for receptor binding. LanthioPep is a Lactococcus lactis based lanthionine-peptide technology and is used to discover peptide therapeutics with increased resistance to peptidase degradation, high receptor specificity, and increased intrinsic activity.

Lanthio Pharma has generated stable, peptidase-resistant lanthionine peptides with specific agonistic activity for a number of GPCR targets, which is a focus area of the company. Many peptide ligands are thought to bind to their GPCR receptors through a "turn motif," which can be stabilized in Lanthio Pharma's peptides with a strong thioether bond. Fixing the turn motif in its optimal receptor binding conformation can result in specific agonistic receptor activation, according to the company. The technology also includes a proprietary bacterial display library capability, which allows for the construction of focused or randomized libraries of lanthionine-peptides. These libraries allow for functional screening and production of peptides for further in vivo and in vitro testing. Therapeutic plasma levels of lantipeptides can potentially be achieved by oral, pulmonary, or subcutaneous delivery. Therapeutic products in Lanthio Pharma's pipeline include a lanthionine-stabilized specific agonist of the AT2 receptor, which has potential in diseases where tissue protection is important, such as fibrosis.

Under the agreement, MorphoSys and Lanthio Pharma will jointly apply their respective technologies to establish lantipeptide-based libraries. MorphoSys received preferred rights to exclusively license the LanthioPep technology for drug discovery and made an equity investment for a minority stake in Lanthio Pharma. Lanthio Pharma also is partnered with US-based Tarix Pharmaceuticals for Lanthio's lead compound PanCyte, a lanthionine-stabilized angiotensin-(1-7) agonistic peptide for treating pulmonary indications. The start of clinical development of PanCyte is expected this year, according to company information.


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