Vasoactive intestinal peptide reduced SARS-CoV-2 infection in cell culture by downregulating and physically removing the virus's entry receptors (ACE2 and TMPRSS2) from cell surfaces.
Dual antiviral mechanismVIP both downregulates production of and physically strips viral entry receptors (ACE2/TMPRSS2) from cell surfaces
What the researchers found
Vasoactive intestinal peptide (VIP) reduced SARS-CoV-2 infection of epithelial cells through a dual mechanism. First, VIP downregulated both ACE2 and TMPRSS2 — the two proteins the virus uses to enter cells — at both the mRNA and surface protein levels. Second, VIP upregulated a protease called ADAM10, which physically strips ACE2 and TMPRSS2 from the cell surface (a process called shedding).
The combined effect of these two mechanisms — reduced production plus active removal — resulted in fewer viral entry points on cell surfaces and a measurably reduced infection rate when cells were challenged with a SARS-CoV-2 pseudovirus. The researchers suggest the ADAM10 connection may have implications beyond COVID-19.
Why it matters
VIP has already been tested in COVID-19 clinical trials based on its known anti-inflammatory properties, but this study reveals an entirely new mechanism: VIP doesn't just dampen the inflammatory response to infection, it may actually reduce viral entry itself by stripping the virus's doorway proteins off cell surfaces. The ADAM10 shedding mechanism is particularly interesting because it could apply to other viruses that use ACE2 or TMPRSS2 for cell entry.
The numbers in context
ACE2 and TMPRSS2 mRNA downregulated · Surface expression of both proteins reduced · ADAM10 upregulated · SARS-CoV-2 pseudovirus infection rate reduced
How the study worked
Researchers used CaCo-2 epithelial cells (a human intestinal cell line) stimulated with SARS-CoV-2 spike protein and treated with native VIP. They measured mRNA expression of ACE2 and TMPRSS2, surface protein expression of both, TMPRSS2 enzyme activity, ADAM10 expression, and infection rates using a SARS-CoV-2 pseudovirus system.
Who was studied
CaCo-2 human epithelial cell line
What this study cannot tell us
This is an in-vitro study using a single cell line (CaCo-2 intestinal cells), which may not reflect the complexity of SARS-CoV-2 infection in lungs or other organs. A pseudovirus was used rather than live SARS-CoV-2. No animal or human data was generated. The study doesn't establish optimal VIP doses for antiviral effects or whether these effects can be achieved in living organisms.
How to read the evidence
This is a preliminary in-vitro study using a single cell line and pseudovirus system. While the dual mechanism is mechanistically compelling, no animal or human data supports these findings yet. The ADAM10 connection is novel but needs in vivo validation.
When this study was published
Published in 2025. Very recent research that adds new mechanistic understanding to VIP's potential role in COVID-19, building on earlier clinical trials that focused on VIP's anti-inflammatory effects.
The bigger picture
VIP was already being studied for COVID-19 because it calms the dangerous immune overreaction (cytokine storm) that kills patients with severe infections. This study adds a second reason VIP might help: it could reduce viral entry itself. If confirmed in vivo, VIP would be a rare therapeutic that addresses both viral replication and inflammatory damage simultaneously. The ADAM10 mechanism is also relevant beyond COVID-19, as ACE2 is involved in heart and kidney diseases.
Questions still open
- Can VIP achieve these ACE2/TMPRSS2-reducing effects in living organisms at therapeutically achievable concentrations?
- Does VIP's ADAM10-mediated shedding mechanism protect against other ACE2-dependent viruses?
- Could VIP-based therapy complement existing COVID-19 treatments by addressing both viral entry and inflammation?
Common questions
How does VIP reduce COVID-19 infection in this study?
Is VIP being used to treat COVID-19 in patients?
Read the original research
Vasoactive Intestinal Peptide (VIP) in COVID-19 Therapy-Shedding of ACE2 and TMPRSS2 via ADAM10.
International journal of molecular sciences, 26(6)
Citation
Gutzler, Charlotte; Höhne, Kerstin; Bani, Daniele; Kayser, Gian; Fähndrich, Sebastian; Ambros, Michael; Hug, Martin J; Rieg, Siegbert; Falcone, Valeria; Müller-Quernheim, Joachim; Zissel, Gernot; Frye, Björn C. (2025). Vasoactive Intestinal Peptide (VIP) in COVID-19 Therapy-Shedding of ACE2 and TMPRSS2 via ADAM10.. International journal of molecular sciences, 26(6). https://doi.org/10.3390/ijms26062666