Betting on Stapled Peptides
Why, then, is Roche making a play for more peptide-based therapeutics? Complexity aside, multiple factors have sparked interest in peptides including the decreasing number of approved drugs produced by the pharmaceutical industry, increasing R&D expenses, and demands for alternative approaches to improve pharmaceutical R&D productivity.
An unmet challenge in peptide drug development has been to access intracellular target space, according to Tomi K. Sawyer, Ph.D., Aileron’s CSO and svp, drug discovery and innovative technologies. Further requirements include achievement of good pharmacokinetic properties and preservation of the peptide’s unique 3-D structural integrity to effect molecular recognition including protein-protein interactions.
“Over the past 30 years lead peptides were successfully identified and chemical manipulations including now classic types of macrocyclization and restricted conformational approaches were used to stabilize them,” Dr. Sawyer pointed out to GEN. “But from the drug development standpoint they didn’t provide the big home run that large pharma or biotech was looking for. Small molecules have been a major competition as peptides have generally lacked the combination of key properties such as metabolic stability, oral absorption, and good pharmacokinetics of small molecule drugs.”
New synthetic strategies for limiting peptide breakdown and allowing oral administration have emerged in recent years. Aileron’s stapled peptide platform stabilizes these molecules into biologically active alpha-helical conformations, reportedly endowing them with good drug-like properties including resistance to proteolytic degradation, improved pharmacokinetics, and cell penetration. The chemistry to achieve a novel peptide structure using hydrocarbon stapling is exquisitely simple, Dr. Sawyer explained.
“We start with a peptide, an alpha-helical conformation, and identify the amino acid residues that are nearest neighbors in the helical conformation, even though they may be separated by a single or double turn. We then replace the helically defined neighboring amino acids with novel side chains that incorporate terminal double bonds (olefins), which, when reacted with special catalysts, generate hydrocarbon macrocycles.”
Dr. Sawyer noted that Aileron is advancing its lead stapled mimetic peptide program to target and modulate intracellular BCL-2 target families/pathways, which are recognized, he said, as very promising targets for cancer treatment. Roche is betting on Aileron’s technology in the hope that hydrocarbon stapling and other innovative strategies for enhancing stability, efficacy, and intracellular delivery may usher in a new era in peptide therapeutics.