Characterisation and evaluation of antiviral recombinant peptides based on the heptad repeat regions of NDV and IBV fusion glycoproteins

Abstract

Mixed virus infections can cause livestock losses that are more devastating than those caused by single virus infections. Newcastle disease virus (NDV) and infectious bronchitis virus (IBV), serious threats to the poultry industry, can give rise to complex mixed infections that hinder diagnosis and prevention. In this study, we show that newly designed peptides, which are based on the heptad repeat (HR) region of the fusion glycoproteins from NDV and IBV, have more potent antiviral activity than the mother HR peptides. Plaque formation and chicken embryo infectivity assays confirmed these results. The novel peptides completely inhibited single virus infections and mixed infections caused by NDV and IBV. Furthermore, we assessed cell toxicity and possible targets for the peptides, thereby strengthening the notion that HR2 is an attractive site for therapeutic intervention. These results suggest the possibility of designing a relatively broad-spectrum class of antiviral peptides that can reduce the effects of mixed-infections.

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

“…We also assessed possible targets for these peptides. Our data strengthened the notion that HR2 is an attractive site for therapeutic intervention (5).…”

“…An untagged peptide (AU, referred to as N2 in a previous report [5]) was synthesized by 9-fluorenylmethoxy carbonyl/tert-butyl group chemistry with the peptide synthesizer SYMPHONY. The Wang resin was mixed with a 3-fold molar excess of protecting amino acids, a 10-fold molar excess of N,N-dimethylpyridin-4-amine and N,N=-dicyclohexylcarbodiimide in dimethylformamide (DMF).…”

“…Class I envelope viruses have similar mechanisms of membrane fusion, in which a key step is the formation of a six-helix bundle of three heptad repeat 1 (HR1) and HR2 trimers of the fusion glycoproteins (1,2,3). The current paradigm of the mechanism of HR-derived peptide action proposes that HR peptides bind to the postulated extended intermediate state after the fusion peptide has been inserted into the target membrane and prevent the transition to the postfusion conformation (3,4,5). The successful use of enfuvirtide against HIV has stimulated considerable efforts to develop more potent peptides (6,7,8,9).…”

Interaction Domain of Glycoproteins gB and gH of Marek's Disease Virus and Identification of an Antiviral Peptide with Dual Functions

“…In this study, we developed HR-based EK modification peptides of gHH1-EK, gHH3-EK, and gBH1-EK. For EK modified residues at the solvent-accessible sites of b, c, f and g (Figure 1C), a series of systematic replacements with double hydrophilic glutamic acid (E) or lysine (K) were introduced to enhance the α-helicity of the peptides by intrahelical salt bridges [30]. At the same time, the interaction sites ( a, d, e ) of these peptides remained intact.…”

Identification and application of self-binding zipper-like sequences in SARS-CoV spike protein

“…Their abilities to conduct sequence-specific interactions have been exploited and been further developed into peptidyl therapeutics and biochemical reagents (Azzarito et al, 2013;Hakoshima, 2001). For anti-viral applications, Leu/Ile zipper-like sequences within HRs have successfully been developed as entry inhibitors against infections such as the human immunodeficiency virus type I and SARS-CoV (Borrego et al, 2013;Bosch et al, 2004;Liu et al, 2005Liu et al, , 2004Medinas et al, 2002;Wang et al, 2011;Wild et al, 1994;Yao and Compans, 1996;Young et al, 1999). Specifically, the HR-derived Leu/Ile zipper-like peptides can bind to the fusion glycoprotein in a dominant-negative fashion, and thereby halt the viral entry and infection.…”