ACERT Highlights: Recent Highlights

National Institute of General Medical Sciences
	National Biomedical Resource for Advanced ESR Spectroscopy

Recent Highlights

Novel Class of Broad-Spectrum Antivirals Improves Enveloped Virus Vaccine Development

Enveloped viruses can cause devastating zoonotic diseases and are most likely to cause global pandemics. We identified XM antivirals as a new class of small-molecule sulfur-containing compounds that broadly inhibit enveloped viruses. The mechanism of inhibition was explored via multidisciplinary approaches including membrane incorporation, membrane fluidity, electron microscopy, electron spin resonance, lipidomics, cytotoxicity, plaque, and conformational antibody analyses. Evidently, the antivirals increase membrane order deep within the hydrophobic region of the bilayer, increase the membrane phase transition temperature, and alter the lipid chemical composition, all inhibiting membrane fusion and viral entry, while leaving the glycoproteins and viral genomes largely unaffected. Consequently, we tested whether these features would lead to effective inactivated enveloped virus vaccines. As a model, we generated an inactivated influenza virus (IIV) vaccine using XM-01 (XM-01-IIV) and compared this to traditional paraformaldehyde (PFA)-inactivated, control compound-inactivated, and live virus vaccines, using a mouse influenza model. Excitingly, XM-01-IIV vaccination improved neutralizing antibody responses against both hemagglutinin and neuraminidase, and decreased mouse morbidity and mortality following IAV challenge, as compared to the other IIV vaccines. Thus, we present a novel class of broadly acting antivirals ideal for generating highly potent enveloped virus inactivated vaccines, particularly for the important negative-stranded RNA viruses.

Publication: A. Pacheco, I.A. Monreal, D.W. Buchholtz, S. Xu, E.M. Contreras, B. Imbiakha, J. Sahler, M. Jager, A.L. Lai, B. Cook, E. Ralalage, Q. Liu, Y.Y. Yeo, A. Ma, J.L. Zamora, N.K. Shil, S. Jones-Burrage, S.M. Pritchard, C. Yang, Y. Zhao, Z.J. Mohamed, C. Xu, S. Daniel, M.J. Jung, G. VandeWalle, A. August, T. Mukhopadhyay, M. Shimamura, A. Goodman, M. Hardy, S. Bose, A.V. Nicola, J.H. Freed, J.W. Jones, M. Xian, and H.C. Aguilar. Under review, Nature Biotechnology

Figure: (A) Comparison of ESR spectra in POPC/POPG (4:1) MLV without (black) or with (red) 5% XM-01 (mol: mol ratio) binding. (B) XM-01 causes an increase in membrane order at various lipid ratios. (C) XM-01 increased the phase transition temperature of both pure POPC and POPC/POPG (4:1) membranes, (right) without (black) or with (red) XM-01. P <0.005. (D) The reaction between butylamine and XM-01 decomposes XM-01, creating disulfide and polysulfide molecules; subsequently, perthiyl radicals are formed.

Armando Pacheco (Flow Cytometry Facility, Institute of Biotechnology, Cornell University, Ithaca, New York)
Isaac A. Monreal, David W. Buchholz (Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY)
Shi Xu (Department of Chemistry, Brown University, Providence, RI)
Erik M. Contreras, Brian Imbiakha, Julie Sahler, Mason Jager (Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY)
Alex Liqi Lai (ACERT)
Brandan Cook (Mathematics, Engineering, Sciences, & Health (MESH) Division, Olympic University, Bremerton, WA)
Elshan Ralalage (Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA)
Qian Liu (Department of Chemistry, University of British Columbia, Vancouver)
Yao Yu Yeo, Andrew Ma, Juana L. Zamora (Department of Microbiology and Immunology, Cornell University, Ithaca, NY)
Niraj K. Shil (Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA)
Sara Jones-Burrage (Department of Biology, Indiana University, Bloomington, IN)
Suzanne M. Pritchard (Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington)
Chuntao Yang (Department of Chemistry, Washington State University)
Yu Zhao (Washington State University)
Zeinab J. Mohamed, Cheyan Xu, Susan Daniel (Department of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY)
Michael J. Jung (Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA)
Gerlinde Van de Walle, Avery August (Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY)
Suchetana T. Mukhopadhyay (Department of Biology, Indiana University-Bloomington, Bloomington, IN)
Masako Shimamura (Infectious Diseases, Nationwide Childrens Hospital, Columbus, OH)
Alan Goodman (School of Molecular Biosciences, Washington State University)
Michele Hardy (College of Letters, Sciences & Professional Studies, Montana Technological University, Butte, MT)
Santanu Bose, Anthony V. Nicola (Department of Veterinary Microbiology and Pathology, Washington State University)
Jack H. Freed (ACERT)
Jace W. Jones (Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD)
Ming Xian (Department of Chemistry, Brown University, Providence, RI)
Hector C. Aguilar (Department of Microbiology and Immunology, Cornell University, Ithaca, NY)

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ACERT is supported by grant 1R24GM146107 from the National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health.

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