A Novel, Broad-Acting Peptide Inhibitor of Double-Stranded DNA Virus Gene Expression and Replication

Abstract

Viral infections are a global disease burden with only a limited number of antiviral agents available. Due to newly emerging viral pathogens and increasing occurrence of drug resistance, there is a continuous need for additional therapeutic options, preferably with extended target range. In the present study, we describe a novel antiviral peptide with broad activity against several double-stranded DNA viruses. The 22-mer peptide TAT-I24 potently neutralized viruses such as herpes simplex viruses, adenovirus type 5, cytomegalovirus, vaccinia virus, and simian virus 40 in cell culture models, while being less active against RNA viruses. The peptide TAT-I24 therefore represents a novel and promising drug candidate for use against double-stranded DNA viruses.

Blocking HSV-1 glycoprotein K binding to signal peptide peptidase reduces virus infectivity in vitro and in vivo

“…In this study we have used TAT peptide as a control and we did not observe any antiviral activity associated with using three different strains of HSV-1, three different cell lines and two different strains of mice. Similar to this study, TAT alone did not have any antiviral activity against two different strains of HSV-1, adenovirus type 5, cytomegalovirus, vaccinia virus, and simian virus 40 in cell culture models [46]. In addition, no antiviral activities associated with the TAT control peptide was reported for influenza virus [47,48], Ebola virus [49], Epstein-Barr virus [50], or Japanese encephalitis virus [51].…”

The Peptide TAT-I24 with Antiviral Activity against DNA Viruses Binds Double-Stranded DNA with High Affinity

“…The linear, 9-mer peptide I24 comprising the sequence CLAFYACFC (Figure 1) was identified as an inhibitor of "foreign" gene expression due to its ability to selectively block transcription from a transfected eukaryotic plasmid-DNA when added together with the DNA to the transfection reaction [23].…”

“…Earlier data have shown that coupling of I24 to a cationic peptide, such as the TAT peptide (residues 48-60) from the HIV-1 transactivator protein (Figure 1), can strongly enhance the inhibitory effect of I24 on gene expression from a eukaryotic expression plasmid transfected with the peptide into cells. Moreover, coupling of I24 to TAT (TAT-I24; Figure 1) not only affected transfected DNA but also exerted a broad-spectrum antiviral activity against several double-stranded DNA viruses, including herpes simplex viruses, cytomegalovirus, vaccinia virus, adenovirus type 5 and SV 40 polyomavirus, an effect which was not seen with I24 alone [23]. It was, therefore, speculated that the TAT peptide contributes to the antiviral effects of the fusion peptide.…”

“…Earlier data indicated that entry of murine cytomegalovirus (MCMV) is affected by TAT-I24, visualised by a virus containing an mCherry-labelled capsid [23]. To address any possible interaction of the peptide TAT-I24 with the viral DNA, cells were infected with a bromodeoxyuridine (BrdU)-labelled MCMV expressing luciferase [41].…”

“…This peptide inhibits replication of multiple, taxonomically diverse doublestranded DNA viruses, including herpes simplex virus, cytomegalovirus, adenovirus type 5, SV40 polyomavirus and vaccinia virus. The proposed mode-of-action suggested that the peptide can affect early steps during or after viral entry but may also be internalised with the virus where it interacts with the viral genome to inhibit subsequent events such as viral gene expression [23]. The present study, therefore, aimed to pinpoint the hypothesised interaction of this peptide with double-stranded DNA and to elucidate its antiviral mechanism of action at the early stages of the viral life cycle.…”