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Biological Chemistry

Strategy Makes A Protein-Based Drug Last Longer In Mice

Replacing certain amino acids in a repeating pattern preserves drug’s shape and activity

by Carmen Drahl
June 23, 2014 | A version of this story appeared in Volume 92, Issue 25

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Credit: Courtesy of Ross Cheloha
This X-ray crystal structure shows a parathyroid hormone fragment (yellow) binding to a portion of its receptor (gray). The positions where β-amino acids would be in a modified version are marked in blue.
This x-ray crystal structure shows a parathyroid harmone fragment (yellow) binding to a portion of its receptor (gray). The places where β-amino acids were incorporated by Sam Gellman et al were digitally mapped in blue. The β-amino acids were not present in the original structure.
Credit: Courtesy of Ross Cheloha
This X-ray crystal structure shows a parathyroid hormone fragment (yellow) binding to a portion of its receptor (gray). The positions where β-amino acids would be in a modified version are marked in blue.

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.

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