title: Conjugation of weak ligands with weak antigens to activate TLR-7: A step toward better vaccine adjuvants.
abstract: To study the structure-activity relationship (SAR) of Toll-like receptor 7 (TLR-7) agonists based on 8-oxoadenines, a novel subset of C9-substituted 8-hydroxy-2-(2-methoxyethoxy)-adenines and their antigen conjugates were synthesized. In vitro, the ability of cytokines (IL-12p70 and IFN-γ) induction of ligands with alkyl acid at C9-position were very weak compared with benzoic acid counter parts. Unexpectedly, its antigen conjugates that conjugated with proteins or peptides with weak immunogenicity, showed enhanced activity of cytokines induction. After administered systemically in mice in vivo, all conjugates induced prolonged increase in pro-inflammatory cytokines and antigen-specific IgG levels in serum compared with free compounds. Results from molecular dynamics (MD) simulations further confirmed the conclusion and provided the details of interaction to explain the phenomenon of experiment. In conclusion, we discovered that TLR-7 could be activated via some conjugates of weak ligand and weak antigen, which could be safer adjuvant candidates for vaccines in the future.
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China; Shenzhen Hornetcorn Biotechnology Co., Ltd., Shenzhen 518045, China. Electronic address: gaodong5211@126.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China; Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Li
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Gao
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Diao
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China.
authors.forename: Zhulin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China. Electronic address: jinhuac@gmail.com.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Shenzhen University Cancer Research Center, Shenzhen 518060, China. Electronic address: gyjin@szu.edu.cn.
authors.forename: Guangyi
authors.initials: G
authors.lastname: Jin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000737:chemistry*; D000818:Animals; D000941:Antigens / Q000737:chemistry*; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D014612:Vaccines / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D016207:Cytokines; D018796:Immunoconjugates; D007074:Immunoglobulin G; D008024:Ligands; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D014612:Vaccines; C002992:8-hydroxyadenine; D000225:Adenine
keywords: Adenine derivative; Adjuvant; Immunostimulatory activity; Toll-like receptor