Novel peptide inhibitor of human tumor necrosis factor-α has antiarthritic activity

Author:

Sahu Debasis,Gupta Charu,Yennamalli Ragothaman M.,Sharma Shikha,Roy Saugata,Hasan Sadaf,Gupta Pawan,Sharma Vishnu Kumar,Kashyap Sujit,Kumar Santosh,Dwivedi Ved Prakash,Zhao Xiangli,Panda Amulya Kumar,Das Hasi Rani,Liu Chuan-Ju

Abstract

AbstractThe inhibition of tumor necrosis factor (TNF)-α trimer formation renders it inactive for binding to its receptors, thus mitigating the vicious cycle of inflammation. We designed a peptide (PIYLGGVFQ) that simulates a sequence strand of human TNFα monomer using a series of in silico methods, such as active site finding (Acsite), protein–protein interaction (PPI), docking studies (GOLD and Flex-X) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNFα. Fluorescence-activated cell sorting and fluorescence microscopy revealed that the peptide effectively inhibited the binding of TNF to the cell surface receptors. The cell culture assays showed that the peptide significantly inhibited the TNFα-mediated cell death. In addition, the nuclear translocation of the nuclear factor kappa B (NFκB) was significantly suppressed in the peptide-treated A549 cells, as observed in immunofluorescence and gel mobility-shift assays. Furthermore, the peptide protected against joint damage in the collagen-induced arthritis (CIA) mouse model, as revealed in the micro focal-CT scans. In conclusion, this TNFα antagonist would be helpful for the prevention and repair of inflammatory bone destruction and subsequent loss in the mouse model of CIA as well as human rheumatoid arthritis (RA) patients. This calls upon further clinical investigation to utilize its potential effect as an antiarthritic drug.

Funder

DST-SERB Young Scientist Award

DST-SERB

DBT

Publisher

Springer Science and Business Media LLC

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