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Discovery of Cyclic Peptide Inhibitors Targeted on TNFα-TNFR1 from Computational Design and Bioactivity Verification
Jiangnan Zhang1, Huijian Zhao1, Qianqian Zhou1
1Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Abstract:
Activating tumor necrosis factor receptor 1 (TNFR1) with tumor necrosis factor alpha (TNFα) is one of the key pathological mechanisms resulting in the exacerbation of rheumatoid arthritis (RA) immune response. Despite various types of drugs being available for the treatment of RA, a series of shortcomings still limits their application. Therefore, developing novel peptide drugs that target TNFα-TNFR1 interaction is expected to expand therapeutic drug options. In this study, the detailed interaction mechanism between TNFα and TNFR1 was elucidated, based on which, a series of linear peptides were initially designed. To overcome its large conformational flexibility, two different head-to-tail cyclization strategies were adopted by adding a proline-glycine (GP) or cysteine-cysteine (CC) to form an amide or disulfide bond between the N-C terminal. The results indicate that two cyclic peptides, R1_CC4 and α_CC8, exhibit the strongest binding free energies. α_CC8 was selected for further optimization using virtual mutations through in vitro activity and toxicity experiments due to its optimal biological activity. The L16R mutant was screened, and its binding affinity to TNFR1 was validated using ELISA assays. This study designed a novel cyclic peptide structure with potential anti-inflammatory properties, possibly bringing an additional choice for the treatment of RA in the future.
Insights
Researchers developed novel cyclic peptides to block the interaction between tumor necrosis factor alpha (TNFα) and its receptor (TNFR1), offering a potential new treatment for rheumatoid arthritis (RA). These peptides show promise for reducing inflammation associated with RA.
Area of Science:
- Biochemistry
- Immunology
- Drug Discovery
Background:
- Tumor necrosis factor receptor 1 (TNFR1) activation by tumor necrosis factor alpha (TNFα) exacerbates rheumatoid arthritis (RA) immune responses.
- Existing RA treatments have limitations, necessitating novel therapeutic strategies.
- Targeting the TNFα-TNFR1 interaction offers a promising avenue for developing new RA drugs.
Purpose of the Study:
- To elucidate the interaction mechanism between TNFα and TNFR1.
- To design and develop novel cyclic peptides targeting the TNFα-TNFR1 interaction for potential RA treatment.
- To optimize and validate the efficacy of designed peptides.
Main Methods:
- Detailed analysis of the TNFα-TNFR1 interaction mechanism.
- Design of linear peptides followed by head-to-tail cyclization using proline-glycine (GP) or cysteine-cysteine (CC) strategies.
- In vitro activity, toxicity, and binding affinity assays (ELISA) for peptide evaluation and optimization.
Main Results:
- Two cyclic peptides, R1_CC4 and α_CC8, demonstrated strong binding free energies with TNFR1.
- The α_CC8 peptide showed optimal biological activity and was selected for further optimization.
- The L16R mutant of α_CC8 exhibited validated binding affinity to TNFR1.
Conclusions:
- Novel cyclic peptides targeting the TNFα-TNFR1 interaction were successfully designed.
- The developed cyclic peptides possess potential anti-inflammatory properties.
- This study presents a promising new therapeutic option for rheumatoid arthritis treatment.
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