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Antimicrob Agents Chemother
. 2025 Jun 23:e0170024.
doi: 10.1128/aac.01700-24. Online ahead of print. Synthetic host defense peptide inhibits SARS-CoV-2 replication in vitro
Rhodri Harfoot 1 , Blair Lawley 1 , Leonor C Hernández 2 , Joanna Kuang 1 3 , Francesca R Hills 1 , Shubhra Sinha 1 , Margot J M Allais 1 4 , Tom W Bird 3 , Cody P Hird 5 , John A Taylor 6 , Mihnea Bostina 1 , Davide Comoletti 3 , Evan F Haney 7 , Robert E W Hancock 7 , Daniel Pletzer 1 , Miguel E Quiñones-Mateu 5
Affiliations
Although myriads of potential antiviral agents have been tested against SARS-CoV-2, only a handful have proven to be effective in clinical trials. During the COVID-19 pandemic, many known or novel peptides were evaluated for their ability to inhibit SARS-CoV-2 replication; however, testing of D-enantiomers that resist body and viral proteases has been limited. Here, we characterized the ability of D-3006, a D-enantiomeric synthetic host defense peptide, to inhibit SARS-CoV-2 replication in vitro. A battery of authentic SARS-CoV-2 variants (ancestral, Mu, Delta, and Omicron BA.1) and a comprehensive panel of β-coronavirus spike pseudotyped lentiviruses were used to demonstrate that D-3006 safely (CC50value = 430 µg/mL) blocked spike-mediated entry (EC50 values ranging from 1.57 to 5.37 µg/mL) and also had synergistic anti-SARS-CoV-2 activity in vitro when combined with the viral polymerase inhibitor remdesivir. We also showed that D-3006 inhibited influenza A virus (H1N1) replication in vitro, suggesting that this synthetic host defense peptide could have potential broad antiviral activity against multiple enveloped viruses. These data, together with negative-stain transmission electron microscopy analysis, suggest that the mechanism of action of D-3006 is associated with non-specific binding to the viral membrane, most likely causing virus aggregation and interfering with virus attachment and entry. The potential broad-spectrum antiviral activity of D-3006, its innate resistance to host proteases, as well as the possibility of being used in combination with other antiviral drugs suggest that this host synthetic peptide could be developed as a candidate for the treatment of SARS-CoV-2 and/or other respiratory viral infections.
Keywords: COVID-19; SARS-CoV-2; antiviral; host defense peptides; influenza virus.
. 2025 Jun 23:e0170024.
doi: 10.1128/aac.01700-24. Online ahead of print. Synthetic host defense peptide inhibits SARS-CoV-2 replication in vitro
Rhodri Harfoot 1 , Blair Lawley 1 , Leonor C Hernández 2 , Joanna Kuang 1 3 , Francesca R Hills 1 , Shubhra Sinha 1 , Margot J M Allais 1 4 , Tom W Bird 3 , Cody P Hird 5 , John A Taylor 6 , Mihnea Bostina 1 , Davide Comoletti 3 , Evan F Haney 7 , Robert E W Hancock 7 , Daniel Pletzer 1 , Miguel E Quiñones-Mateu 5
Affiliations
- PMID: 40548715
- DOI: 10.1128/aac.01700-24
Although myriads of potential antiviral agents have been tested against SARS-CoV-2, only a handful have proven to be effective in clinical trials. During the COVID-19 pandemic, many known or novel peptides were evaluated for their ability to inhibit SARS-CoV-2 replication; however, testing of D-enantiomers that resist body and viral proteases has been limited. Here, we characterized the ability of D-3006, a D-enantiomeric synthetic host defense peptide, to inhibit SARS-CoV-2 replication in vitro. A battery of authentic SARS-CoV-2 variants (ancestral, Mu, Delta, and Omicron BA.1) and a comprehensive panel of β-coronavirus spike pseudotyped lentiviruses were used to demonstrate that D-3006 safely (CC50value = 430 µg/mL) blocked spike-mediated entry (EC50 values ranging from 1.57 to 5.37 µg/mL) and also had synergistic anti-SARS-CoV-2 activity in vitro when combined with the viral polymerase inhibitor remdesivir. We also showed that D-3006 inhibited influenza A virus (H1N1) replication in vitro, suggesting that this synthetic host defense peptide could have potential broad antiviral activity against multiple enveloped viruses. These data, together with negative-stain transmission electron microscopy analysis, suggest that the mechanism of action of D-3006 is associated with non-specific binding to the viral membrane, most likely causing virus aggregation and interfering with virus attachment and entry. The potential broad-spectrum antiviral activity of D-3006, its innate resistance to host proteases, as well as the possibility of being used in combination with other antiviral drugs suggest that this host synthetic peptide could be developed as a candidate for the treatment of SARS-CoV-2 and/or other respiratory viral infections.
Keywords: COVID-19; SARS-CoV-2; antiviral; host defense peptides; influenza virus.