Targeting Tumor Necrosis Factor Receptor 1 with Selected Aptamers for Anti-Inflammatory Activity

  • ACS Appl Mater Interfaces. 2023 Feb 22. doi: 10.1021/acsami.3c00131.
Xiao Chu  1  2 ,  Xinyu Du  2 ,  Longhua Yang  1 ,  Ziyi Wang  1 ,  Yi Zhang  1 ,  Xiaonan Wang  1 ,  Lijun Dai  1 ,  Jiangnan Zhang  1 ,  Jie Liu  2 ,  Nan Zhang  1 ,  Yongxing Zhao  1 ,  Hongzhou Gu  2  3
Affiliations
  • 1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 2. Fudan University Shanghai Cancer Center, and Institutes of Biomedical Sciences, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China.
  • 3. School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
PMID: 36812453 DOI: 10.1021/acsami.3c00131
Abstract

Tumor necrosis factor-α (TNFα) inhibitors are widely used in treating autoimmune diseases like rheumatoid arthritis (RA). These inhibitors can presumably alleviate RA symptoms by blocking TNFα-TNF receptor 1 (TNFR1)-mediated pro-inflammatory signaling pathways. However, the strategy also interrupts the survival and reproduction functions conducted by TNFα-TNFR2 interaction and causes side effects. Thus, it is urgently needed to develop inhibitors that can selectively block TNFα-TNFR1 but not TNFα-TNFR2. Here, nucleic acid-based Aptamers against TNFR1 are explored as potential anti-RA candidates. Through the systematic evolution of ligands by exponential enrichment (SELEX), two types of TNFR1-targeting Aptamers were obtained, and their KD values are approximately 100-300 nM. In silico analysis shows that the binding interface of aptamer-TNFR1 highly overlapped with natural TNFα-TNFR1 binding. On the cellular level, the Aptamers can exert TNFα inhibitory activity by binding to TNFR1. The anti-inflammatory efficiencies of Aptamers were assessed and further enhanced using divalent aptamer constructs. These findings provide a new strategy to block TNFR1 for potential anti-RA treatment precisely.

Keywords
SELEX; TNFR1; anti-inflammation; aptamer; molecular simulation; rheumatoid arthritis.
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