Structure-activity relationship of synthetic toll-like receptor 4 agonists.
Important questions remain regarding the impact of variations in the structure of the lipid A portion of lipopolysaccharide on activation of cells via the Toll-like receptor 4 complex. We have studied a series of synthetic lipid A mimetic compounds known as aminoalkyl glucosaminide phosphates in which the length of the secondary acyl chain has been systematically varied. Using transcriptional profiling of human monocytes and responses of Toll-like receptor 4 complex cell transfectants, we demonstrate a clear dependence of length on secondary acyl chain on Toll-like receptor 4 activation. Compounds with secondary acyl chains less than eight carbons in length have dramatically reduced activity, and substitutions of the left-sided secondary acyl chain had the most important effect on the Toll-like receptor 4 agonist activity of these molecules. The structure-function relationships of these compounds assessed via the induction of chemokines and cytokines following in vivo administration closely mirrored those seen with cell-based studies. This novel set of synthetic lipid A mimetics will be useful for Toll-like receptor 4-based investigations and may have clinical utility as stand-alone immunomodulators.
Corixa Corporation, Seattle, Washington 98104, USA.
Axel G
AG
Stöver
Jean
J
Da Silva Correia
Jay T
JT
Evans
Christopher W
CW
Cluff
Mark W
MW
Elliott
Eric W
EW
Jeffery
David A
DA
Johnson
Michael J
MJ
Lacy
Jory R
JR
Baldridge
Peter
P
Probst
Richard J
RJ
Ulevitch
David H
DH
Persing
Robert M
RM
Hershberg
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists*; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D000276:Adjuvants, Immunologic; D016207:Cytokines; D008050:Lipid A; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha