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Abstract
Unnatural oligomers that can mimic protein surfaces offer a potentially useful strategy for blocking biomedically important protein-protein 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.
Footnotes
- 1To whom correspondence should be addressed. E-mail: gellman{at}chem.wisc.edu
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Author contributions: W.S.H., L.M.J., P.J.K., M.L., J.P.M., and S.H.G. designed research; W.S.H., L.M.J., T.J.K., and M.L. performed research; W.S.H., L.M.J., P.J.K., M.L., J.P.M., and S.H.G. analyzed data; and W.S.H. and S.H.G. wrote the paper.
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Edited by David Baker, University of Washington, Seattle, WA, and approved July 2, 2009
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers
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