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. 2012;7(5):e36833.
doi: 10.1371/journal.pone.0036833. Epub 2012 May 16.

A general strategy to endow natural fusion-protein-derived peptides with potent antiviral activity

Antonello Pessi  1 , Annunziata Langella, Elena Capitò, Silvia Ghezzi, Elisa Vicenzi, Guido Poli, Thomas Ketas, Cyrille Mathieu, Riccardo Cortese, Branka Horvat, Anne Moscona, Matteo Porotto
Affiliations

A general strategy to endow natural fusion-protein-derived peptides with potent antiviral activity

Antonello Pessi et al. PLoS One. 2012.

Abstract

Fusion between the viral and target cell membranes is an obligatory step for the infectivity of all enveloped virus, and blocking this process is a clinically validated therapeutic strategy.Viral fusion is driven by specialized proteins which, although specific to each virus, act through a common mechanism, the formation of a complex between two heptad repeat (HR) regions. The HR regions are initially separated in an intermediate termed "prehairpin", which bridges the viral and cell membranes, and then fold onto each other to form a 6-helical bundle (6HB), driving the two membranes to fuse. HR-derived peptides can inhibit viral infectivity by binding to the prehairpin intermediate and preventing its transition to the 6HB.The antiviral activity of HR-derived peptides differs considerably among enveloped viruses. For weak inhibitors, potency can be increased by peptide engineering strategies, but sequence-specific optimization is time-consuming. In seeking ways to increase potency without changing the native sequence, we previously reported that attachment to the HR peptide of a cholesterol group ("cholesterol-tagging") dramatically increases its antiviral potency, and simultaneously increases its half-life in vivo. We show here that antiviral potency may be increased by combining cholesterol-tagging with dimerization of the HR-derived sequence, using as examples human parainfluenza virus, Nipah virus, and HIV-1. Together, cholesterol-tagging and dimerization may represent strategies to boost HR peptide potency to levels that in some cases may be compatible with in vivo use, possibly contributing to emergency responses to outbreaks of existing or novel viruses.

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Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: Antonello Pessi is the owner of a small company (PeptiPharma) and the holder of the intellectual properties for the cholesterol addition and the dimerization of peptides. Annunziata Langella is currently an employe at Merck Serono and, Elena Capitò is currently an employe at BASF Italy. They do not hold any intellectual properties regarding the cholesterol tagged peptides and do not have any other competing interest. Anne Moscona and Matteo Porotto receive funds from NIH to study the antiviral properties of the fusion inhibitor peptides. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Synthesis of the dimeric cholesterol-tagged fusion inhibitors via conjugation of a cysteine-containing peptide precursor to the maleimide-functionalized core 9.
Figure 2
Figure 2. Inhibition of type 3 HPIV envelope glycoproteins mediated fusion by the HRC-derived fusion inhibitors HPIV-P2 (○), the monomeric cholesterol-tagged fusion inhibitor HPIV-P3 (•), the dimeric fusion inhibitor HPIV-P5 (□), and the dimeric cholesterol-tagged inhibitor HPIV-P4 (▪).
The percent inhibition of fusion (compared to control cells not treated with peptide) is shown as a function of the (log-scale) concentration of peptide. The values are means (±SD) of the results from three experiments.
Figure 3
Figure 3. Inhibition of Nipah virus envelope glycoproteins mediated fusion by the HPIV-3 HRC-derived fusion inhibitors HPIV-P2 (○), the monomeric cholesterol-tagged fusion inhibitor HPIV-P3 (•), the dimeric fusion inhibitor HPIV-P5 (□), and the dimeric cholesterol-tagged inhibitor HPIV-P4 (▪).
The percent inhibition of fusion (compared to control cells not treated with peptide) is shown as a function of the (log-scale) concentration of peptide. The values are means (±SD) of the results from three experiments.
Figure 4
Figure 4. Inhibition of HIV infectivity by the fusion inhibitor HIV-P2 (▪), the monomeric cholesterol-tagged inhibitor HIV-P3 (p), the dimeric fusion inhibitor HIV-P5 (•), and the dimeric cholesterol-tagged inhibitor HIV-P4 (⧫).
The efficiency of virus infection is shown as relative luciferase units (RLU) as a function of the (log-scale) concentration of peptide.
Figure 5
Figure 5. In vivo efficacy of the dimeric cholesterol-tagged peptide.
HPIV-P4 (•) was given intraperitoneally to groups of 5 hamsters concurrently with live NiV infection. Injections of the inhibitor were then repeated every day for up to 10 days post infection. Control animals were injected with vehicle alone (untreated, □) or with peptide without NiV infection (mock infected, Δ). Treatment with the dimeric cholesterol tagged peptide led to a statistically significant increase of survival compared to non treated infected animals (Chi2 test = **P value = 0.008).
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