3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant activities.
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.
Johnson
D A
DA
Pharmaceutical Discovery Division, Ribi ImmunoChem Research, Inc., 553 Old Corvallis Road, Hamilton, Montana 59840, USA. dajohn@corixa.com
Keegan
D S
DS
Sowell
C G
CG
Livesay
M T
MT
Johnson
C L
CL
Taubner
L M
LM
Harris
A
A
Myers
K R
KR
Thompson
J D
JD
Gustafson
G L
GL
Rhodes
M J
MJ
Ulrich
J T
JT
Ward
J R
JR
Yorgensen
Y M
YM
Cantrell
J L
JL
Brookshire
V G
VG
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008050:Lipid A / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011817:Rabbits; D012475:Salmonella / Q000737:chemistry; D013329:Structure-Activity Relationship; D013745:Tetanus Toxoid; D014611:Vaccination
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007074:Immunoglobulin G; D008050:Lipid A; D013745:Tetanus Toxoid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse