Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate View Full Text


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Article Info

DATE

2018-02-20

AUTHORS

Benjamin L. Oyler, Mohd M. Khan, Donald F. Smith, Erin M. Harberts, David P. A. Kilgour, Robert K. Ernst, Alan S. Cross, David R. Goodlett

ABSTRACT

Recent advances in lipopolysaccharide (LPS) biology have led to its use in drug discovery pipelines, including vaccine and vaccine adjuvant discovery. Desirable characteristics for LPS vaccine candidates include both the ability to produce a specific antibody titer in patients and a minimal host inflammatory response directed by the innate immune system. However, in-depth chemical characterization of most LPS extracts has not been performed; hence, biological activities of these extracts are unpredictable. Additionally, the most widely adopted workflow for LPS structure elucidation includes nonspecific chemical decomposition steps before analyses, making structures inferred and not necessarily biologically relevant. In this work, several different mass spectrometry workflows that have not been previously explored were employed to show proof-of-principle for top down LPS primary structure elucidation, specifically for a rough-type mutant (J5) E. coli-derived LPS component of a vaccine candidate. First, ion mobility filtered precursor ions were subjected to collision induced dissociation (CID) to define differences in native J5 LPS v. chemically detoxified J5 LPS (dLPS). Next, ultra-high mass resolving power, accurate mass spectrometry was employed for unequivocal precursor and product ion empirical formulae generation. Finally, MS3 analyses in an ion trap instrument showed that previous knowledge about dissociation of LPS components can be used to reconstruct and sequence LPS in a top down fashion. A structural rationale is also explained for differential inflammatory dose-response curves, in vitro, when HEK-Blue hTLR4 cells were administered increasing concentrations of native J5 LPS v. dLPS, which will be useful in future drug discovery efforts.Graphical Abstractᅟ More... »

PAGES

1221-1229

References to SciGraph publications

  • 2014-08-06. Inflammatory caspases are innate immune receptors for intracellular LPS in NATURE
  • 2016-04-07. Analysis of Bacterial Lipooligosaccharides by MALDI-TOF MS with Traveling Wave Ion Mobility in JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
  • 2015-06-20. 21 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer: A National Resource for Ultrahigh Resolution Mass Analysis in JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
  • 2002-11-01. Bacterial strategies for overcoming host innate and adaptive immune responses in NATURE IMMUNOLOGY
  • 1993-05. Cross-reactivity of monoclonal antibodies and sera directed against lipid A and lipopolysaccharides in INFECTION
  • 2007-06-01. Structural heterogeneity and environmentally regulated remodeling of Francisella tularensis subspecies novicida lipid a characterized by tandem mass spectrometry in JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
  • 2016-12-06. Autopiquer - a Robust and Reliable Peak Detection Algorithm for Mass Spectrometry in JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
  • 2010-06-10. Development of an Anti-Endotoxin Vaccine for Sepsis in ENDOTOXINS: STRUCTURE, FUNCTION AND RECOGNITION
  • 2008-08-01. Putting endotoxin to work for us: Monophosphoryl lipid A as a safe and effective vaccine adjuvant in CELLULAR AND MOLECULAR LIFE SCIENCES
  • 2009-03-01. The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex in NATURE
  • 1988-12. A systematic nomenclature for carbohydrate fragmentations in FAB-MS/MS spectra of glycoconjugates in GLYCOCONJUGATE JOURNAL
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    http://scigraph.springernature.com/pub.10.1007/s13361-018-1897-y

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    http://dx.doi.org/10.1007/s13361-018-1897-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1101127827

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29464544


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