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

Area of Science:

• Biotechnology
• Immunology
• Drug Discovery

Background:

• Tumor necrosis factor-α (TNFα) inhibitors are standard treatments for rheumatoid arthritis (RA).
• Current TNFα inhibitors block both TNFα-TNFR1 and TNFα-TNFR2 interactions, leading to side effects by disrupting TNFR1's survival and reproduction roles.
• Selective inhibition of TNFα-TNFR1 signaling is needed to improve RA treatment efficacy and safety.

Purpose of the Study:

• To explore nucleic acid-based aptamers as selective inhibitors of TNFR1 for potential RA therapy.
• To develop aptamers that specifically block TNFα-TNFR1 pro-inflammatory pathways while sparing TNFα-TNFR2 interactions.

Main Methods:

• Systematic evolution of ligands by exponential enrichment (SELEX) was used to identify TNFR1-targeting aptamers.
• In silico analysis was performed to evaluate aptamer-TNFR1 binding interfaces.
• Cellular assays were conducted to assess aptamer-mediated TNFα inhibition and anti-inflammatory activity.
• Divalent aptamer constructs were synthesized to enhance anti-inflammatory efficiency.

Main Results:

• Two types of TNFR1-targeting aptamers were successfully obtained with dissociation constants (K_D) in the range of 100-300 nM.
• In silico analysis confirmed that aptamer-TNFR1 binding interfaces closely mimic natural TNFα-TNFR1 interactions.
• Aptamers demonstrated TNFα inhibitory activity on a cellular level by binding to TNFR1.
• Divalent aptamer constructs showed enhanced anti-inflammatory effects.

Conclusions:

• Nucleic acid aptamers targeting TNFR1 represent a promising new strategy for selective blockade of pro-inflammatory signaling in RA.
• These aptamers offer a precise therapeutic approach by inhibiting TNFα-TNFR1 interactions without affecting TNFR1's beneficial functions.
• The findings support the development of aptamer-based therapeutics for RA with potentially improved safety and efficacy profiles.