title: Synthesis and Evaluation of Conjugates of Novel TLR7 Inert Ligands as Self-Adjuvanting Immunopotentiators.
abstract: During the design and synthesis of a series of 8-hydroxy-2-(2-methoxyethoxy)-adenine derivatives bearing various substituted -RCOOH groups at the 9-position, we identified a TLR7-inert ligand, which does not activate TLR7 signaling pathway. Of interest, the coupling of weakly immunogenic antigens via the -RCOOH group was able to significantly enhance the immunogenicity of the antigens. Herein, an inert ligand, 9-(3-carboxypropyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine (5, GD2), was synthesized and conjugated to 5 different weakly immunogenic antigens (BSA, OVA, MSA, MG7, and thymosin). Compared with the GD2 and the potent agonist UC-1 V150, all conjugates demonstrated potent immunogenicity in vitro and in vivo. All conjugates induced prolonged increases, while UC-1 V150 showed a rapid decline in the levels of proinflammatory cytokines following initial increases. These data indicate that the immunostimulatory activity of TLR7-inert ligands could be amplified and prolonged by conjugation to antigens, thus broadening the potential therapeutic application of these agents.
authors: Shenzhen University Cancer Research Center , Institute of Otorhinolaryngology, Shenzhen 518060, China ; Sun Yat-sen University Cancer Center , Guangzhou 510060, China.
authors: Dong
authors: D
authors: Gao
authors: Shenzhen University Cancer Research Center , Institute of Otorhinolaryngology, Shenzhen 518060, China ; Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education, College of Optoelectronic Engineering, Shenzhen University , Shenzhen 518060, China.
authors: Yu
authors: Y
authors: Liu
authors: Shenzhen University Cancer Research Center , Institute of Otorhinolaryngology, Shenzhen 518060, China.
authors: Yuwen
authors: Y
authors: Diao
authors: Shenzhen University Cancer Research Center , Institute of Otorhinolaryngology, Shenzhen 518060, China.
authors: Ningning
authors: N
authors: Gao
authors: Shenzhen University Cancer Research Center , Institute of Otorhinolaryngology, Shenzhen 518060, China.
authors: Zhulin
authors: Z
authors: Wang
authors: Shenzhen University Cancer Research Center , Institute of Otorhinolaryngology, Shenzhen 518060, China ; Sun Yat-sen University Cancer Center , Guangzhou 510060, China.
authors: Wenqi
authors: W
authors: Jiang
authors: Shenzhen University Cancer Research Center , Institute of Otorhinolaryngology, Shenzhen 518060, China.
authors: Guangyi
authors: G
authors: Jin
keywords: Toll-like receptor agonist; adenine derivative; immunostimulatory activity