Strategy Makes A Protein-Based Drug Last Longer In Mice

Polypeptide drugs rarely endure in the bloodstream for long without help from chemists, but strategies for extending these drugs’ half-lives work better on some peptides than others. One challenging polypeptide is the osteoporosis medication Forteo (teriparatide). It has a half-life of less than 30 minutes. Its structure—a lengthy α-helix—is critical for its bioactivity, but the usual modification tool kit does a poor job at keeping that motif intact. Now, researchers have strategically modified the peptide’s backbone and extended its half-life in mice (Nat. Biotechnol. 2014, DOI: 10.1038/nbt.2920). Samuel H. Gellman of the University of Wisconsin, Madison; Thomas J. Gardella of Harvard Medical School; and colleagues replaced a handful of the α-amino acids in teriparatide’s active ingredient, a fragment of parathyroid hormone, with β-amino acids. They used an α-α-α-β pattern that causes β-residues to spiral around the helix’s periphery. Gellman’s team had previously demonstrated that this pattern preserves helices’ shape. This study “paves the way for the design of metabolically stable mimics of various other helical peptide hormones and helical proteins in general,” says Paramjit Arora of New York University, an expert in helix mimicry.