HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 6, 4440-4449, February 6, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/6/4440    most recent M310760200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stöver, A. G. Articles by Hershberg, R. M. Search for Related Content PubMed PubMed Citation Articles by Stöver, A. G. Articles by Hershberg, R. M. Social Bookmarking                      What's this?

Structure-Activity Relationship of Synthetic Toll-like Receptor 4 Agonists^*

Axel G. Stöver, Jean Da Silva Correia, Jay T. Evans¶, Christopher W. Cluff¶, Mark W. Elliott, Eric W. Jeffery, David A. Johnson¶, Michael J. Lacy¶, Jory R. Baldridge¶, Peter Probst, Richard J. Ulevitch, David H. Persing||** , and Robert M. Hershberg||**

From the Corixa Corporation, Seattle, Washington 98104, ^¶Corixa Corporation, Hamilton, Montana 59840, Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, and ^||The Infectious Disease Research Institute, Seattle, Washington 98104

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.

Received for publication, September 30, 2003

^* This work was supported by Defense Advanced Research Projects Agency Contract N66001-01-C-8007 (to D. H. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Both authors contributed equally to this work.

To whom correspondence and reprint requests may be addressed: Corixa Corp., 1124 Columbia St., Suite 200, Seattle, WA 98104. Tel.: 206-754-5879; Fax: 206-754-5917; E-mail: persing{at}corixa.com. To whom correspondence may be addressed: Dendreon Corp., 3005 First Ave., Seattle, WA 98121. Tel.: 206-829-1625; Fax: 206-219-7200; E-mail: rhershberg{at}dendreon.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. A. J. O'Neill, C. E. Bryant, and S. L. Doyle Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer Pharmacol. Rev., June 1, 2009; 61(2): 177 - 197. [Abstract] [Full Text] [PDF]

				N. Resman, J. Vasl, A. Oblak, P. Pristovsek, T. L. Gioannini, J. P. Weiss, and R. Jerala Essential Roles of Hydrophobic Residues in Both MD-2 and Toll-like Receptor 4 in Activation by Endotoxin J. Biol. Chem., May 29, 2009; 284(22): 15052 - 15060. [Abstract] [Full Text] [PDF]

				L. Sweet, W. Zhang, H. Torres-Fewell, A. Serianni, W. Boggess, and J. Schorey Mycobacterium avium Glycopeptidolipids Require Specific Acetylation and Methylation Patterns for Signaling through Toll-like Receptor 2 J. Biol. Chem., November 28, 2008; 283(48): 33221 - 33231. [Abstract] [Full Text] [PDF]

				A. Lembo, M. Pelletier, R. Iyer, M. Timko, J. C. Dudda, T. E. West, C. B. Wilson, A. M. Hajjar, and S. J. Skerrett Administration of a Synthetic TLR4 Agonist Protects Mice from Pneumonic Tularemia J. Immunol., June 1, 2008; 180(11): 7574 - 7581. [Abstract] [Full Text] [PDF]

				B. Zhang, G. Ramesh, S. Uematsu, S. Akira, and W. B. Reeves TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity J. Am. Soc. Nephrol., May 1, 2008; 19(5): 923 - 932. [Abstract] [Full Text] [PDF]

				R. S. Munford Sensing Gram-Negative Bacterial Lipopolysaccharides: a Human Disease Determinant? Infect. Immun., February 1, 2008; 76(2): 454 - 465. [Full Text] [PDF]

				S. M. Zughaier, B. Lindner, J. Howe, P. Garidel, M. H.J. Koch, K. Brandenburg, and D. S. Stephens Physicochemical characterization and biological activity of lipooligosaccharides and lipid A from Neisseria meningitidis Innate Immunity, December 1, 2007; 13(6): 343 - 357. [Abstract] [PDF]

				M. S. Trent, C. M. Stead, A. X. Tran, and J. V. Hankins Invited review: Diversity of endotoxin and its impact on pathogenesis Innate Immunity, August 1, 2006; 12(4): 205 - 223. [Abstract] [PDF]

				Y. Rosenfeld, N. Papo, and Y. Shai Endotoxin (Lipopolysaccharide) Neutralization by Innate Immunity Host-Defense Peptides: PEPTIDE PROPERTIES AND PLAUSIBLE MODES OF ACTION J. Biol. Chem., January 20, 2006; 281(3): 1636 - 1643. [Abstract] [Full Text] [PDF]

				B. S. Thompson, P. M. Chilton, J. R. Ward, J. T. Evans, and T. C. Mitchell The low-toxicity versions of LPS, MPL(R) adjuvant and RC529, are efficient adjuvants for CD4+ T cells J. Leukoc. Biol., December 1, 2005; 78(6): 1273 - 1280. [Abstract] [Full Text] [PDF]

				J. D. Savov, D. M. Brass, B. L. Lawson, E. McElvania-Tekippe, J. K. L. Walker, and D. A. Schwartz Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L329 - L337. [Abstract] [Full Text] [PDF]

				R. E. Bishop, S.-H. Kim, and A. El Zoeiby Role of lipid A palmitoylation in bacterial pathogenesis Innate Immunity, June 1, 2005; 11(3): 174 - 180. [Abstract] [PDF]

				S. M. Zughaier, S. M. Zimmer, A. Datta, R. W. Carlson, and D. S. Stephens Differential Induction of the Toll-Like Receptor 4-MyD88-Dependent and -Independent Signaling Pathways by Endotoxins Infect. Immun., May 1, 2005; 73(5): 2940 - 2950. [Abstract] [Full Text] [PDF]

				K. Kawasaki, R. K. Ernst, and S. I. Miller Deacylation and palmitoylation of lipid A by Salmonellae outer membrane enzymes modulate host signaling through Toll-like receptor 4 Innate Immunity, December 1, 2004; 10(6): 439 - 444. [Abstract] [PDF]

				K. Kawasaki, R. K. Ernst, and S. I. Miller 3-O-Deacylation of Lipid A by PagL, a PhoP/PhoQ-regulated Deacylase of Salmonella typhimurium, Modulates Signaling through Toll-like Receptor 4 J. Biol. Chem., May 7, 2004; 279(19): 20044 - 20048. [Abstract] [Full Text] [PDF]