Year: 2009
Type: article
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.
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: bronze
Awards: G102163711, G1286251239, Novel Agonists and Inverse Agonists for B-Family GPCRs, G2287611682, G262962599, Structure & Function of the HIV-1 Envelope Protein, Modified envelope glycoproteins for HIV-1 vaccine, G426311843, A practical microbicide based on HIV-1 entry inhibitors, G498139845, G5182022505, G5387317844, Structure and Function of the HIV-1 Envelope Protein, Beta-Peptide Inhibitors of Protein-Protein Interactions, G6848031779, G6918803902, G7583137537, Chemistry-Biology Interface Training Program, G969889393, G993149817
OpenAlex ID: W2050486326