Designer peptides could save failed drug candidates

When it comes to developing a new medicine, designing the active compound is only half the battle. “Many potential therapeutic compounds are hydrophobic—oily—so they’re not very stable in aqueous environments,” says Naxhije Berisha, who earned her PhD under the mentorship of Rein Ulijn at the City University of New York and Daniel Heller at Memorial Sloan Kettering Cancer Center. “You need something to stabilize it so it can be delivered to the cells [without] precipitating in the blood and causing unwanted toxic side effects.”

Excipients, the extra ingredients added to the final drug formulation, are powerful tools to enhance the drug performance. But finding a safe and effective combination is no trivial matter. Researchers led by Ulijn and Heller have now developed a series of peptides that can work as anticancer excipients, with each peptide matched to specific drug properties to create tailored nanoparticles for drug delivery (Chem 2025, DOI: 10.1016/j.chempr.2024.102404).

Berisha began by emulating the key structural features of an existing small-molecule excipient with short peptide chains. She found that the chains containing aromatic amino acids like tryptophan were the most stabilizing. “I chose the other amino acids based on varying charge or rigidity properties,” she says.

Spectroscopic studies revealed that the most promising peptide conformations contained three alternating or three central tryptophan residues, and the team then screened a shortlist of eight of these structures against 25 preclinical drugs. Of the 184 formulations tested, 69 produced nanoparticles with the required properties.

Using molecular dynamics simulations, Berisha probed the structure and formation of these successful nanoparticles further. Hydrophobic interactions, particularly those involving tryptophan residues, drive the self-assembly process, forming 100 nm particles with a charged surface and greasy interior. The remainder of the peptide chains, which make up just 2% of the total mass, arrange predominantly at the particle surface, modulating the nanocarrier’s physical properties like size, degree of dispersion, and stability. After the release of the drug cargo, the peptide carrier degrades into its constituent amino acids, a process likely mediated by protease enzymes in the blood.

With the “what” and “how” established, the team sought a final proof-of-concept demonstration, investigating two formulations of the anticancer tyrosine inhibitor lestaurtinib in mice. On its own, lestaurtinib, which had failed clinical trials because of low bioavailability, did not noticeably affect tumor size, but when it was incorporated in either peptide formulation, it dramatically reduced cancer growth, even at lower dose frequencies.

Moving forward, the researchers hope this same peptide-matching approach could be applied to other failed drug candidates. “We’ve really tried to figure out the rules for drug and peptide matching, not through correlation but through understanding the physical chemistry,” Ulijn says. “There are plenty of very promising drugs which have failed because of poor bioavailability, and we’re hoping that maybe it’s possible to rescue some of those by this approach.”

For Ravi Kumar, a drug delivery scientist at the University of Alabama, this research is a very timely addition to the field. “There are numerous advances in drug discovery, but those are not met by the discovery in excipients,” he says. “This research is exceptional and aptly fits into the current landscape of new drug discovery portfolios. [Next] they need to look at scalability and storing dosage forms in terms of addressing a particular disease.”