Literature DB >> 34421287

Synthesis, structure-activity relationship studies and evaluation of a TLR 3/8/9 agonist and its analogues.

Anindya Sarkar1, Anushka C Galasiti Kankanamalage1, Qian Zhang2, Heng Cheng2, Prasanna Sivaprakasam3, Joseph Naglich3, Chunshan Xie3, Sanjeev Gangwar2, Dale L Boger1.   

Abstract

A comprehensive SAR study of a putative TLR 3/8/9 agonist was conducted. Despite the excitement surrounding the potential of the first small molecule TLR3 agonist with a compound that additionally displayed agonist activity for TLR8 and TLR9, compound 1 displayed disappointing activity in our hands, failing to match the potency (EC50) reported and displaying only a low efficacy for the extent of stimulated NF-κB activation and release. The evaluation of >75 analogs of 1, many of which constitute minor modifications in the structure, failed to identify any that displayed significant activity and none that exceeded the modest activity found for 1.

Entities:  

Keywords:  SAR study; TLR agonists; TLR3 agonist; Toll-like receptor (TLR)

Year:  2021        PMID： 34421287      PMCID： PMC8372028          DOI： 10.1007/s00044-021-02736-3

Source DB:  PubMed          Journal:  Med Chem Res        ISSN： 1054-2523            Impact factor:   2.351


  29 in total

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Review 5.  Structural biology of the Toll-like receptor family.

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Journal:  Annu Rev Biochem       Date:  2011       Impact factor: 23.643

6.  Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in mice.

Authors:  Ying Wang; Lijing Su; Matthew D Morin; Brian T Jones; Yuto Mifune; Hexin Shi; Kuan-Wen Wang; Xiaoming Zhan; Aijie Liu; Jianhui Wang; Xiaohong Li; Miao Tang; Sara Ludwig; Sara Hildebrand; Kejin Zhou; Daniel J Siegwart; Eva Marie Y Moresco; Hong Zhang; Dale L Boger; Bruce Beutler
Journal:  Proc Natl Acad Sci U S A       Date:  2018-08-27       Impact factor: 11.205

7.  Structural Basis of TLR2/TLR1 Activation by the Synthetic Agonist Diprovocim.

Authors:  Lijing Su; Ying Wang; Junmei Wang; Yuto Mifune; Matthew D Morin; Brian T Jones; Eva Marie Y Moresco; Dale L Boger; Bruce Beutler; Hong Zhang
Journal:  J Med Chem       Date:  2019-03-13       Impact factor: 7.446

Review 8.  TLR2 agonists and their structure-activity relationships.

Authors:  Benjamin L Lu; Geoffrey M Williams; Margaret A Brimble
Journal:  Org Biomol Chem       Date:  2020-07-15       Impact factor: 3.876

Review 9.  More than complementing Tolls: complement-Toll-like receptor synergy and crosstalk in innate immunity and inflammation.

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Journal:  Immunol Rev       Date:  2016-11       Impact factor: 12.988

Review 10.  Modulation of the Innate Immune Response by Targeting Toll-like Receptors: A Perspective on Their Agonists and Antagonists.

Authors:  Stefano Federico; Luca Pozzetti; Alessandro Papa; Gabriele Carullo; Sandra Gemma; Stefania Butini; Giuseppe Campiani; Nicola Relitti
Journal:  J Med Chem       Date:  2020-09-15       Impact factor: 7.446
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