Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers

W. Seth Horne, Lisa M. Johnson, Thomas J. Ketas, Per Johan Klasse, Min Lu, John P. Moore, Samuel H. Gellmana

Research output: Contribution to journalArticlepeer-review

229 Scopus citations


Unnatural oligomers that can mimic protein surfaces offer a potentially useful strategy for blocking biomedically important proteinprotein interactions. Here we evaluate an approach based on combining α- and β-amino acid residues in the context of a polypeptide sequence from the HIV protein gp41, which represents an excellent testbed because of the wealth of available structural and biological information. We show that α/β-peptides can mimic structural and functional properties of a critical gp41 subunit. Physical studies in solution, crystallographic data, and results from cell-fusion and virus-infectivity assays collectively indicate that the gp41-mimetic α/β-peptides effectively block HIV-cell fusion via a mechanism comparable to that of gp41-derived α-peptides. An optimized α/β-peptide is far less susceptible to proteolytic degradation than is an analogous α-peptide. Our findings show how a two-stage design approach, in which sequence-based α→β replacements are followed by site-specific backbone rigidification, can lead to physical and biological mimicry of a natural biorecognition process.

Original languageEnglish (US)
Pages (from-to)14751-14756
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
StatePublished - Sep 1 2009


  • Alpha/beta-peptides
  • HIV
  • Protein folding
  • Protein-protein interactions


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