A Short Double-Stapled Peptide Inhibits Respiratory Syncytial Virus Entry and Spreading.
Antimicrob Agents Chemother
; 61(4)2017 04.
Article
in En
| MEDLINE
| ID: mdl-28137809
ABSTRACT
Synthetic peptides derived from the heptad repeat (HR) of fusion (F) proteins can be used as dominant negative inhibitors to inhibit the fusion mechanism of class I viral F proteins. Here, we have performed a stapled-peptide scan across the HR2 domain of the respiratory syncytial virus (RSV) F protein with the aim to identify a minimal domain capable of disrupting the formation of the postfusion six-helix bundle required for viral cell entry. Constraining the peptides with a single staple was not sufficient to inhibit RSV infection. However, the insertion of double staples led to the identification of novel short stapled peptides that display nanomolar potency in HEp-2 cells and are exceptionally robust to proteolytic degradation. By replacing each amino acid of the peptides by an alanine, we found that the substitution of residues 506 to 509, located in a patch of polar contacts between HR2 and HR1, severely affected inhibition. Finally, we show that intranasal delivery of the most potent peptide to BALB/c mice significantly decreased RSV infection in upper and lower respiratory tracts. The discovery of this minimal HR2 sequence as a means for inhibition of RSV infection provides the basis for further medicinal chemistry efforts toward developing RSV fusion antivirals.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Peptides
/
Viral Fusion Proteins
/
Respiratory Syncytial Virus, Human
/
Respiratory Syncytial Virus Infections
/
Virus Internalization
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Antimicrob Agents Chemother
Year:
2017
Document type:
Article
Affiliation country:
Switzerland