Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists

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 a-helix mi...

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Vydáno v:Journal of medicinal chemistry Ročník 59; číslo 10; s. 4812 - 4830
Hlavní autoři: Morin, Matthew D., Wang, Ying, Jones, Brian T., Su, Lijing, Surakattula, Murali M. R. P., Berger, Michael, Huang, Hua, Beutler, Elliot K., Zhang, Hong, Beutler, Bruce, Boger, Dale L.
Médium: Journal Article
Jazyk:angličtina
Vydáno: WASHINGTON Amer Chemical Soc 26.05.2016
Témata:
Aminobutyrates - chemical synthesis
Aminobutyrates - chemistry
Aminobutyrates - pharmacology
Animals
Benzamides - chemical synthesis
Benzamides - chemistry
Benzamides - pharmacology
Chemistry, Medicinal
Dose-Response Relationship, Drug
Drug Discovery
Humans
Life Sciences & Biomedicine
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Ovalbumin - immunology
Pharmacology & Pharmacy
Science & Technology
Structure-Activity Relationship
Toll-Like Receptor 4 - agonists
ADAPTIVE IMMUNITY
MONOPHOSPHORYL-LIPID-A
ACTIVATION
ENDOTOXIN ANTAGONIST
BINDING-PROTEIN
TLR4-MD-2 COMPLEX
VACCINE ADJUVANTS
TARGETING PROTEIN-PROTEIN
LPS
INNATE IMMUNITY
ISSN:0022-2623, 1520-4804, 1520-4804
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Popis
Shrnutí: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 a-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.
Bibliografie:NIH RePORTER
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.6b00177