A Cholesterol Tag at the N Terminus of the Relatively Broad-Spectrum Fusion Inhibitory Peptide Targets an Earlier Stage of Fusion Glycoprotein Activation and Increases the Peptide's Antiviral Potency In Vivo

Abstract

In previous work, we designed peptides that showed potent inhibition of Newcastle disease virus (NDV) and infectious bronchitis virus (IBV) infections in chicken embryos. In this study, we demonstrate that peptides modified with cholesterol or 3 U of polyethylene glycol (PEG 3 ) conjugated to the peptides' N termini showed even more promising antiviral activities when tested in animal models. Both cholesterol-and cholesterol-PEG 3 -tagged peptides were able to protect chicken embryos from infection with different serotypes of NDV and IBV when administered 12 h prior to virus inoculation. In comparison, the untagged peptides required intervention closer to the time of viral inoculation to achieve a similar level of protection. Intramuscular injection of cholesterol-tagged peptide at 1.6 mg/kg 1 day before virus infection and then three times at 3-day intervals after viral inoculation protected 70% of the chickens from NDV infection. We further demonstrate that the cholesterol-tagged peptide has an in vivo half-life greater than that of untagged peptides. It also has the potential to cross the blood-brain barrier to enter the avian central nervous system (CNS). Finally, we show that the cholesterol-tagged peptide could play a role before the viral fusion peptide's insertion into the host cell and thereby target an earlier stage of fusion glycoprotein activation. Our findings are of importance for the further development of antivirals with broad-spectrum protective effects.

Broad spectrum antiviral activity for paramyxoviruses is modulated by biophysical properties of fusion inhibitory peptides

“…The efficacy of N-terminally lipid conjugated fusion inhibitory peptides has been studied for both Ebola21and Newcastle Disease virus23. In the case of Newcastle Disease virus, Li et al .…”

Cellular protein GLTSCR2: A valuable target for the development of broad-spectrum antivirals

“…Enterovirus A71 (EV-A71) strain BC08 , avian influenza virus (AIV) strain H9-WD (Wang et al, 2016b), canine distemper virus (CDV) strain MD77 (Lan et al, 2005), Newcastle disease virus (NDV) strain Lasota and infectious bronchitis virus (IBV) strain M41 (Li et al, 2013), porcine epidemic diarrhea virus (PEDV) strain CV777 (Sun et al, 2015), VSV strain Indiana (Wang et al, 2016a), HSV-1 strain F (Wang et al, 2011) and HCV strain JFH-1 (Xu et al, 2014) are reproduced in RD, MDCK, Vero, HeLa, Vero, HeLa, HEK293T, HeLa and Huh7.5.1 cells respectively, according to the reports indicated above. GFP-NDV strain NA-1 is generated by inserting an additional transcription cassette coding for the enhanced GFP between the P and M genes of the NDV genome (Wang et al, 2015).…”

Three kinds of treatment with Homoharringtonine, Hydroxychloroquine or shRNA and their combination against coronavirus PEDV in intro

“…We have established a concept for developing transfection vectors that may have wide applications in gene antiviral strategies, including the delivery of siRNA to combat viral infection. This approach has the potential to be utilized for the prevention and control of coronavirus PEDV [36]. However, our study demonstrates that the antiviral effect of dual shRNA-expressing plasmids was the same as single shRNA-N.…”

“…Coronavirus S glycoprotein shares a mechanism similar to other Class I virus glycoproteins for membrane fusion [15][16][17]. Our previous work has shown that the modi ed HR peptide e ciently blocks coronavirus infection [17,18].…”