As potential therapeutics, peptides offer many advantages over existing technologies, such as greater specificity than small-molecule drugs. And their small size, typically fewer than 50 amino acids, allows these protein fragments to be made cheaply and taken as pills—something that can't be done with large antibodies and most other biologics. Yet, peptides, in their native state, have an Achilles' heel: they remain prone to unraveling, which leads to their degradation by the cell's clean-up enzymes.

In a clever workaround, a Cambridge, Massachusetts–based startup has come up with a way to lock peptides into certain shapes by introducing chemical 'staples' into their amino acid backbones. And last month, the company, Aileron Therapeutics, announced that it had secured the $12 million it needs to advance its lead stapled-peptide drug into phase 1 testing.

“The clinical trial announcement is great news for the field,” says David Lane, chief scientist at A*STAR in Singapore who also works on stapled-peptide technologies. “This is a new class of potential medicine, and the trial will hopefully establish that they are safe and effective in man.”

The Aileron drug, known as ALRN-5281, is designed to boost the release of human growth hormone in people with rare endocrine disorders. Preclinical data for ALRN-5281, which could replace frequent injections of synthetic hormones, will be presented publicly for the first time later this month at a conference in Japan. Meanwhile, Aileron is also looking at other stapled-peptide candidates for treating cancer, inflammation and various metabolic disorders. Last year, for example, Aileron cofounder Loren Walensky, of the Dana-Farber Cancer Institute in Boston, published a report describing how treatment with a stapled peptide designed to modulate the B-cell lymphoma 2 (BCL-2) pathway led to remission in a mouse model of leukemia (J. Clin. Invest. 122, 2018–2031, 2012).

Pepped up peptides?

Not all the results from stapled peptides are as promising. In November, researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Parkville, Australia, in collaboration with scientists from Genentech in South San Francisco, California, tested a chemically reinforced peptide that, like Walensky's drug, targeted BCL-2 proteins. Unexpectedly, the stapling actually destabilized the peptide in its normal protein state, so it couldn't target and kill cells as well as hoped (ACS Chem. Biol. doi:10.1021/cb3005403, 2012).

Joseph Yanchik, Aileron's president and chief executive, remains unfazed by the findings. “To use the WEHI work as the basis for general conclusions about stapled peptides is a bit of a stretch,” he says, noting that the study used a particular stapled peptide that Walensky's group had previously intentionally weakened for structural experiments.

Genentech's parent company, Roche, doesn't seem too concerned by the data coming from its subsidiary, either. In 2010, the Swiss pharmaceutical giant inked a deal with Aileron worth up to $1.1 billion, and last year the two partners started to present work stemming from the collaboration at scientific meetings. Most recently, in December, Lane and his colleagues showed that stapled peptides can successfully reach and reactivate a tumor-suppressor protein called p53 to block cancer cell growth (ACS Chem. Biol. doi:10.1021/cb3005148, 2012).

The true test, of course, will come later this year when ALRN-5281 enters the clinic. “Promising results from the first series of clinical trials would serve to validate an entirely new therapeutic approach for treating human disease,” Walensky says.