title: Toll-like receptor 7 inactive ligands enhanced cytokine induction by conjugation to weak antigens.
abstract: Toll-like receptors (TLRs) 7/8 are key targets in the design and development of small-molecule drugs serving as anticancer/antiviral agents and vaccine adjuvants. Clinical trials of imiquimod were discontinued owing to its serious adverse side effects. Herein we report the synthesis and biological evaluation of a series of 8-hydroxy-2-(2-methoxyethoxy)adenine derivatives that cannot induce cytokine production and that lack activity toward TLR 7/8. Their ability to triggering remarkable levels of cytokine production were revealed upon their conjugation with antigens that have weak immunogenicity. This discovery demonstrated that TLR 7 can be activated by coupling an antigen to the terminal carboxyl group at N9 of the inactive ligand adenine analogues. These inactive analogues may be well suited as new adjuvants with superior activity after conjugation, effectively decreasing the side effects caused by conventional adjuvants.
authors.affiliation: Cancer Research Center, Shenzhen University, Shenzhen 518060 (P. R. China). gaodong5211@126.com.|Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education, Shenzhen University, Shenzhen 518060 (P. R. China). gaodong5211@126.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Cancer Research Center, Shenzhen University, Shenzhen 518060 (P. R. China).
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Diao
authors.affiliation: Cancer Research Center, Shenzhen University, Shenzhen 518060 (P. R. China).
authors.forename: Wang
authors.initials: W
authors.lastname: Li
authors.affiliation: Cancer Research Center, Shenzhen University, Shenzhen 518060 (P. R. China).
authors.forename: Ningning
authors.initials: N
authors.lastname: Gao
authors.affiliation: Cancer Research Center, Shenzhen University, Shenzhen 518060 (P. R. China).|Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education, Shenzhen University, Shenzhen 518060 (P. R. China).
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cancer Research Center, Shenzhen University, Shenzhen 518060 (P. R. China).
authors.forename: Zhulin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Cancer Research Center, Shenzhen University, Shenzhen 518060 (P. R. China).
authors.forename: Wenqi
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Cancer Research Center, Shenzhen University, Shenzhen 518060 (P. R. China). gyjin@szu.edu.cn.
authors.forename: Guangyi
authors.initials: G
authors.lastname: Jin
mesh_terms: D000941:Antigens / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D008024:Ligands; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D000941:Antigens; D016207:Cytokines; D008024:Ligands; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7
keywords: adenine derivatives; adjuvants; immunostimulatory activity; toll-like receptors