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Nat Commun
. 2026 Jan 6.
doi: 10.1038/s41467-025-67775-5. Online ahead of print. Sulfur-containing class of broad-spectrum antivirals improves influenza virus vaccine development
David W Buchholz # 1 , Armando Pacheco # 1 2 , Sreetama Pal 3 , I Abrrey Monreal 1 , Shi Xu 2 4 , Brian Imbiakha 1 , Julie Sahler 1 , Mason Jager 1 , Alex Liqi Lai 5 , Erik M Contreras 1 , Shahrzad Ezzatpour 1 , Brandan Cook 2 , Elshan Ralalage 6 , Qian Liu 7 , Yao Yu Yeo 1 , Andrew Ma 1 , Haewon Byun 1 , Obaed Shah 1 , J Lizbeth Reyes Zamora 1 , Niraj K Shil 8 , Sara Jones-Burrage 9 , Suzanne M Pritchard 8 , Chuntao Yang 2 , Yu Zhao 2 , Zeinab J Mohamed 3 , Cheyan Xu 3 , Michael J Jung 6 , Gerlinde R Van de Walle 1 , Suchetana Mukhopadhyay 9 , Masako Shimamura 10 , Alan G Goodman 11 , Michele Hardy 12 , Santanu Bose 8 , Anthony V Nicola 8 , Jack H Freed 5 , Avery August 1 , Susan Daniel 3 , Petr Chlanda 13 , Jace W Jones 14 , Ming Xian 2 4 , Hector C Aguilar 15 16
Affiliations
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.
. 2026 Jan 6.
doi: 10.1038/s41467-025-67775-5. Online ahead of print. Sulfur-containing class of broad-spectrum antivirals improves influenza virus vaccine development
David W Buchholz # 1 , Armando Pacheco # 1 2 , Sreetama Pal 3 , I Abrrey Monreal 1 , Shi Xu 2 4 , Brian Imbiakha 1 , Julie Sahler 1 , Mason Jager 1 , Alex Liqi Lai 5 , Erik M Contreras 1 , Shahrzad Ezzatpour 1 , Brandan Cook 2 , Elshan Ralalage 6 , Qian Liu 7 , Yao Yu Yeo 1 , Andrew Ma 1 , Haewon Byun 1 , Obaed Shah 1 , J Lizbeth Reyes Zamora 1 , Niraj K Shil 8 , Sara Jones-Burrage 9 , Suzanne M Pritchard 8 , Chuntao Yang 2 , Yu Zhao 2 , Zeinab J Mohamed 3 , Cheyan Xu 3 , Michael J Jung 6 , Gerlinde R Van de Walle 1 , Suchetana Mukhopadhyay 9 , Masako Shimamura 10 , Alan G Goodman 11 , Michele Hardy 12 , Santanu Bose 8 , Anthony V Nicola 8 , Jack H Freed 5 , Avery August 1 , Susan Daniel 3 , Petr Chlanda 13 , Jace W Jones 14 , Ming Xian 2 4 , Hector C Aguilar 15 16
Affiliations
- PMID: 41495036
- DOI: 10.1038/s41467-025-67775-5
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.