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

Matthew D. Morin(Scripps Research Institute), Ying Wang(The University of Texas Southwestern Medical Center), Brian T. Jones(Scripps Research Institute), Lijing Su(The University of Texas Southwestern Medical Center), Murali Surakattula(Scripps Research Institute), Michael Berger(Scripps Research Institute), Hua Huang(Scripps Research Institute), Elliot K. Beutler(Scripps Research Institute), Hong Zhang(The University of Texas Southwestern Medical Center), Bruce Beutler(The University of Texas Southwestern Medical Center), Dale L. Boger(Scripps Research Institute)
Journal of Medicinal Chemistry
April 6, 2016
Cited by 37Open Access
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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.


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