2. Academic Validation
  3. 3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant activities

3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant activities

  • J Med Chem. 1999 Nov 4;42(22):4640-9. doi: 10.1021/jm990222b.
D A Johnson 1,  D S Keegan,  C G Sowell,  M T Livesay,  C L Johnson,  L M Taubner,  A Harris,  K R Myers,  J D Thompson,  G L Gustafson,  M J Rhodes,  J T Ulrich,  J R Ward,  Y M Yorgensen,  J L Cantrell,  V G Brookshire
Affiliations

Affiliation

  • 1 Pharmaceutical Discovery Division, Ribi ImmunoChem Research, Inc., 553 Old Corvallis Road, Hamilton, Montana 59840, USA. dajohn@corixa.com
PMID: 10579826 DOI: 10.1021/jm990222b
Abstract

The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an Adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific Antibodies in mice.

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