Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers.
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.
Horne
W Seth
WS
Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, USA.
Johnson
Lisa M
LM
Ketas
Thomas J
TJ
Klasse
Per Johan
PJ
Lu
Min
M
Moore
John P
JP
Gellman
Samuel H
SH
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D000998:Antiviral Agents; D015700:HIV Envelope Protein gp41; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1
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