# Sulfur-containing class of broad-spectrum antivirals improves influenza virus vaccine development

## TL;DR

Scientists discovered sulfur-based compounds that can inactivate viruses and improve influenza vaccines by altering viral membranes.

## Contribution

A new class of sulfur-containing antivirals that broadly inhibit enveloped viruses and enhance vaccine development.

## Key findings

- XM compounds alter viral membrane lipid composition and increase membrane order.
- XM-01-IIV vaccine elicits stronger antibody responses than traditional vaccines in mice.
- XM-01-IIV reduces influenza-related morbidity and mortality in mouse models.

## Abstract

Enveloped viruses are significant zoonotic disease threats with the potential to cause global pandemics. We identified a class of small-molecule sulfur-containing antiviral compounds (XM series) that broadly inhibit enveloped viruses. Multidisciplinary approaches revealed that XM compounds alter the viral membrane lipid chemical composition, enhance membrane order within the hydrophobic bilayer, and increase membrane phase transition temperatures. This mechanism inhibits membrane fusion and viral entry, while leaving the viral glycoproteins and genomes largely unaffected. Leveraging these unique properties, we develop a proof-of-concept whole inactivated influenza virus (IIV) vaccine using XM-01 (XM-01-IIV). In a mouse model, XM-01-IIV elicit significantly enhanced neutralizing antibody responses against hemagglutinin and neuraminidase compared to traditional paraformaldehyde-inactivated vaccines. Further, XM-01-IIV reduces morbidity and mortality following influenza challenge, achieving protection comparable to live virus vaccination. This promising class of broadly acting antivirals can be highly impactful in the development of highly potent inactivated vaccines for enveloped viruses.

Improved vaccines and antivirals are needed for many enveloped viruses. Here, the authors identify sulfur-based small molecules that disrupt viral membrane properties, inhibiting fusion and entry, and safely inactivate influenza virus. The resulting inactivated influenza vaccine is protective in mice.