Cyclic defensin peptide RTD-1 activates interferon antiviral pathways and blocks SARS-CoV-2 infection in human cells | Research

The takeaway

Rhesus theta defensin-1 (RTD-1), a cyclic antimicrobial peptide, activates interferon and antiviral gene expression via JAK-STAT1 signaling and IFNAR receptor, inhibiting VSV and SARS-CoV-2 infection in multiple human cell types.

Anti-inflammatory + antiviral dual action
RTD-1 uniquely combines NF-κB inhibition (anti-inflammatory) with JAK-STAT1 interferon activation (antiviral)—ideal for viral diseases where inflammation causes damage

What the researchers found

RTD-1 in human monocytes: ↑interferon and antiviral gene expression (RNA-seq). Mechanism: JAK-dependent STAT1 Y701 phosphorylation, IFNAR-dependent, NF-κB-independent. Antiviral: ↓VSV infection (THP-1), ↓SARS-CoV-2 spike pseudovirus (Vero E6), ↓authentic SARS-CoV-2 (Calu-3).

Why it matters

RTD-1 is unique: it is both anti-inflammatory (inhibits NF-κB) AND antiviral (activates interferon). This dual activity could be valuable for treating viral infections where inflammation itself is damaging, like COVID-19.

How the study worked

RNA-seq of RTD-1-treated human monocytes and THP-1 cells. STAT1 phosphorylation. ISRE reporter assays with JAK inhibitor and IFNAR blockade. Viral infection inhibition assays (VSV, SARS-CoV-2 pseudovirus, authentic SARS-CoV-2).

What this study cannot tell us

In vitro studies. RTD-1 is from rhesus macaques (not human). Human theta defensins are pseudogenes. Bioavailability and delivery challenges. Antiviral potency not quantified.

How to read the evidence

In vitro mechanistic study with RNA-seq, signaling analysis, and multiple viral models. Strong mechanism.

When this study was published

Published in 2025.

The bigger picture

Cyclic antimicrobial peptides with dual anti-inflammatory and antiviral properties could address the central challenge of viral diseases: controlling the pathogen while preventing the inflammatory damage that drives severe disease.

Questions still open

Could synthetic RTD-1 analogues be developed as antiviral drugs?
Does the dual anti-inflammatory + antiviral mechanism work in vivo?
Could RTD-1 treat COVID-19 where inflammation drives disease severity?

Common questions

Can a natural peptide fight COVID-19?

This study shows RTD-1—a cyclic antimicrobial peptide—blocks SARS-CoV-2 infection in human cells by activating the body's interferon antiviral defense. It does this while also reducing inflammation (a key driver of severe COVID-19), making it uniquely suited for viral diseases where the immune response itself causes damage.

What makes RTD-1 special among antimicrobial peptides?

Most AMPs either kill pathogens directly or modulate immunity—but rarely both. RTD-1 is unique because it simultaneously activates antiviral interferon pathways (boosting viral defense) while inhibiting NF-κB inflammatory pathways (reducing tissue damage). This dual action could be transformative for treating viral infections.

Read the original research

The macrocyclic peptide rhesus theta defensin 1 activates interferon and antiviral pathways in human monocytes.

Journal of leukocyte biology, 117(12)

View on PubMed ↗Publisher’s paper ↗

Citation

Tongaonkar, Prasad; Trinh, Katie K; Henley, Jill E; Sell, Philip J; Thakker, Vyoma; Ouellette, André J; Selsted, Michael E. (2025). The macrocyclic peptide rhesus theta defensin 1 activates interferon and antiviral pathways in human monocytes.. Journal of leukocyte biology, 117(12). https://doi.org/10.1093/jleuko/qiaf150