Journal of Medicinal Chemistry p. 1045 - 1060 (2018)
Update date:2022-08-15
Topics:
Foster, Amy J.
Nagata, Masahiro
Lu, Xiuyuan
Lynch, Amy T.
Omahdi, Zakaria
Ishikawa, Eri
Yamasaki, Sho
Timmer, Mattie S. M.
Stocker, Bridget L.
Effective Th1-stimulating vaccine adjuvants typically activate antigen presenting cells (APCs) through pattern recognition receptors (PRRs). Macrophage inducible C-type lectin (Mincle) is a PRR expressed on APCs and has been identified as a target for Th1-stimulating adjuvants. Herein, we report on the synthesis and adjuvanticity of rationally designed brartemicin analogues containing long-chain lipids and demonstrate that they are potent Mincle agonists that activate APCs to produce inflammatory cytokines in a Mincle-dependent fashion. Mincle binding, however, does not directly correlate to a functional immune response. Mutation studies indicated that the aromatic residue of lead compound 9a has an important interaction with Mincle Arg183. In vivo assessment of 9a highlighted the capability of this analogue to augment the Th1 response to a model vaccine antigen. Taken together, our results show that lipophilic brartemicin analogues are potent Mincle agonists and that 9a has superior in vivo adjuvant activity compared to TDB.
View Morewebsite:http://www.sjc.com.tw
Contact:(886) 2-2396-6223
Address:14Fl., No. 99. Sec. 2, Jen Ai Road
Contact:+86-838-5655598
Address:Guanghan Nanfeng Industrial Zone
Jiangxi Global Natural Spice Co., Ltd.
website:https://www.jxhqxl.com/
Contact:+86-796-8106598
Address:No.89, Wenshan Road,South Industrial Park, Jishui County,Jiangxi Province
Shaanxi Lighte Optoelectronics Material Co., Ltd.
Contact:+86-29-88320728-622/619/620
Address:No.55 INDUSTRY ROAD 2,XI'AN NATIONAL CIVIL AEROSPACE INDUSTRIAL PARK.XI'AN China 710065.
WUHU HUAHAI BIOLOGY ENGINEERING CO LTD
Contact:+86-553-3836920
Address:7/F NO.82 LAODONG ROAD WUHU CHINA
Doi:10.1021/jo00132a001
(1982)Doi:10.1139/v82-180
(1982)Doi:10.1039/jr9620000141
(1962)Doi:10.1021/bi00648a040
(1976)Doi:10.1021/ja00015a058
(1991)Doi:10.1021/acs.jmedchem.7b01515
(2018)