title: Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists.
abstract: Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor.
authors.affiliation: Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Morin
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Jones
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
authors.forename: Lijing
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Murali M R P
authors.initials: MM
authors.lastname: Surakattula
authors.affiliation: Department of Genetics, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.affiliation: Department of Genetics, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Elliot K
authors.initials: EK
authors.lastname: Beutler
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000613:Aminobutyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D010047:Ovalbumin / Q000276:immunology; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D000613:Aminobutyrates; D001549:Benzamides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D010047:Ovalbumin