Peptides P4 and P7 derived from E protein inhibit entry of dengue virus serotype 2 via interacting with β3 integrin

Dengue virus (DENV) infection has become a severe public health problem worldwide. However, there is no specific antiviral drug available yet. In this study, we found that DENV serotype 2 (DENV2) infection enhanced the expression of β3 integrin on human umbilical vein endothelial cells (HUVECs) and that DENV2 antigens co-localized with β3 integrin. DENV2 envelope protein (E) directly interacted with β3 integrin, and their interacting sites were located at domain III of E protein (EDIII). Several synthetic peptides were designed based on the amino acid sequence of EDIII, and peptides P4 and P7 could inhibit DENV2 entry into HUVECs in a dose-dependent manner. The inhibitory concentration (IC₅₀) of the two peptides was 19.08 ± 2.52 μM for P4 and 12.86 ± 5.96 μM for P7. Moreover, P7 containing an FG-loop, but not P4, could also inhibit DENV1 entry into HUVECs. Our results suggest a novel mechanism in which interaction between β3 integrin and EDIII is involved in DENV entry. The findings on the inhibitory effect of the peptides on viral entry have significance for anti-DENV drug design.