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Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers.

TitleStructural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers.
Publication TypeJournal Article
Year of Publication2009
AuthorsW Horne S, Johnson LM, Ketas TJ, Klasse PJohan, Lu M, Moore JP, Gellman SH
JournalProc Natl Acad Sci U S A
Volume106
Issue35
Pagination14751-6
Date Published2009 Sep 1
ISSN1091-6490
KeywordsAmino Acid Sequence, Antiviral Agents, Circular Dichroism, Crystallography, X-Ray, HIV Envelope Protein gp41, HIV-1, Models, Molecular, Molecular Mimicry, Molecular Sequence Data, Peptides, Protein Binding, Protein Folding, Protein Structure, Quaternary, Protein Structure, Secondary, Protein Structure, Tertiary
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 alpha- and beta-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 alpha/beta-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 alpha/beta-peptides effectively block HIV-cell fusion via a mechanism comparable to that of gp41-derived alpha-peptides. An optimized alpha/beta-peptide is far less susceptible to proteolytic degradation than is an analogous alpha-peptide. Our findings show how a two-stage design approach, in which sequence-based alpha-->beta replacements are followed by site-specific backbone rigidification, can lead to physical and biological mimicry of a natural biorecognition process.

DOI10.1073/pnas.0902663106
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID19706443
PubMed Central IDPMC2736470
Grant ListAI42382 / AI / NIAID NIH HHS / United States
AI45463 / AI / NIAID NIH HHS / United States
AI76982 / AI / NIAID NIH HHS / United States
CA119875 / CA / NCI NIH HHS / United States
F32 CA119875 / CA / NCI NIH HHS / United States
GM56414 / GM / NIGMS NIH HHS / United States
T32GM008505 / GM / NIGMS NIH HHS / United States

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