Synthetic peptides derived from the heptad repeat (HR) of fusion proteins can be used as dominant negative inhibitors to inhibit the fusion of class II viral pathogens. This strategy has been investigated previously in the case of respiratory syncytial virus (RSV), but it did not lead to potent inhibitors when using native sequences only.
Here, we have performed a stapled peptide scan across the HR-2 domain of the RSV fusion protein with the aim to identify a minimal domain capable of disrupting the formation of the post fusion six helix bundle required for viral cell entry.
We identified two short stapled peptides, 4ca and 4bb, which display nanomolar potency in HEp-2 cells, and are exceptionally robust to degradation in the presence of proteolytic enzymes. Intranasal administration of a rHRSV-Luc virus to BALBc mice in the presence of peptide 4ca resulted in a significant decrease of viral infection.
The sequence of the peptides identified herein are two times shorter than T118, one of the best native peptide reported previously, and are 10 -fold more potent inhibitors. Peptides 4ca and 4bb display similar potency than SAH-RSVBD, a 35-mer double stapled peptide reported previously.