Sulfur-containing class of broad-spectrum antivirals improves influenza virus vaccine development
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.
Authors
- Avery August (ORCID: https://orcid.org/0000-0003-4968-3415)
- Sara E. Jones-Burrage
- Chuntao Yang
- Petr Chlanda (ORCID: https://orcid.org/0000-0002-7782-2139)
- Jace W. Jones (ORCID: https://orcid.org/0000-0003-0460-0380)
- Jack H. Freed (ORCID: https://orcid.org/0000-0003-4288-2585)
- Adia Carrillo Pacheco
- Zeinab Mohamed (ORCID: https://orcid.org/0000-0002-6794-276X)
- Andrew Ma (ORCID: https://orcid.org/0000-0002-0948-2494)
- Sreetama Pal (ORCID: https://orcid.org/0000-0002-7153-1402)
- Cheyan Xu (ORCID: https://orcid.org/0000-0002-0270-9465)
- David W. Buchholz (ORCID: https://orcid.org/0000-0001-8874-6648)
- Susan Daniel (ORCID: https://orcid.org/0000-0001-7773-0835)
- Alex L. Lai
- Elshan Ralalage
- Julie Sahler (ORCID: https://orcid.org/0000-0003-1852-9511)
- Erik Contreras (ORCID: https://orcid.org/0000-0002-3844-3486)
- Masako Shimamura (ORCID: https://orcid.org/0009-0008-9952-351X)
- Brandan M. Cook
- Alan G. Goodman (ORCID: https://orcid.org/0000-0001-6394-332X)
- Suzanne M. Pritchard
- Suchetana Mukhopadhyay (ORCID: https://orcid.org/0000-0001-9230-4746)
- Anthony V. Nicola (ORCID: https://orcid.org/0000-0001-8757-0417)
- Niraj K. Shil
- Yao Yu Yeo (ORCID: https://orcid.org/0000-0002-7604-2296)
- Brian Imbiakha
- M. E. JUNG
- Shi Xu
- Michele E. Hardy
- Haewon Byun
- Mason C. Jager
- Ming Xian
- I. Abrrey Monreal
- Obaed Shah
- Qian Liu
- Santanu Bose
- Gerlinde R. Van de Walle
- Yu Zhao
- Shahrzad Ezzatpour
- Hector C. Aguilar
- J. Lizbeth Reyes Zamora
Institutions
- University of Maryland, Baltimore (US)
- Nationwide Children's Hospital (US)
- University of California, Los Angeles (US)
- Cornell University (US)
- Heidelberg University (DE)
- Brown University (US)
- University Hospital Heidelberg (DE)
- New York State College of Agriculture & Life Sciences (US)
- Indiana University Bloomington (US)
- Washington State University (US)
- Montana Technological University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-06
- DOI
- https://doi.org/10.1038/s41467-025-67775-5
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft