A novel BLyS antagonist peptide designed based on the 3-D complex structure of BCMA and BLyS

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Abstract

B lymphocyte stimulator (BLyS) is a member of tumor necrosis factor (TNF) family. Because of its roles in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren syndrome (SS), BLyS antagonists have been tested to treat SLE- and RA-like symptoms in mice and obtained optimistic results. So far, reported BLyS antagonists were mostly decoyed BLyS receptors or anti-BLyS antibodies. In this study, a novel BLyS antagonist peptide, PT, was designed based on the modeling 3-D complex structure of BCMA and BLyS. The interaction mode of PT with BLyS was analyzed theoretically. The results of competitive ELISA demonstrated that PT could inhibit the binding of BCMA-Fc and anti-BLyS antibody to BLyS in vitro. In addition, PT could partly block the proliferating activity of BLyS on mice splenocytes. The BLyS antagonizing activity of PT was significant (p < 0.05). This study highlights the possibility of using BLyS antagonist peptide to neutralize BLyS activity. Further optimization of PT with computer-guided molecular design method to enhance its biopotency may be useful in developing new BLyS antagonists to treat BLyS-related autoimmune diseases.

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Materials and methods

Reagents. Recombinant BLyS and anti-BLyS monoclonal antibody B7 were prepared as previously described [15]. BCMA-Fc was produced in this laboratory (unpublished data).

A BLyS antagonist peptide design. The BCMA and BLyS coordinates were obtained from the Protein Data Bank (PDB code:1oqd (BCMA), 1kxg (BLyS)). Considered with structural complementary and electrostatic matching while BLyS and BCMA contacted each other, molecular surface character was analyzed using molecular graphics and Delphi

BLyS antagonist peptide designed logically based on key residues of BCMA

The interacting mode of BCMA and BLyS was evaluated and the important amino residues of BCMA/BLyS interaction were determined. Analysis of the Connolly surface complemented by individual amino acid characteristics in the binding pocket revealed noticeable interactions between BLyS and its receptor BCMA, that could be exploited for antagonist design. Dealing with structural matching and electrostatic complementary, the key residues were defined as active chemical groups for the starting point of

Discussion

Blocking BLyS activity by antagonists to treat SLE and RA has been tested in animal model. Administration of decoyed receptors of BLyS, TACI-Fc into SLE-like mice has been demonstrated to improve the symptoms and inhibit the disease development [6], [17]. TACI-Fc also significantly improves the symptoms of RA in animal model [18]. These observations suggest that BLyS may be a potential therapeutic target to treat autoimmune. In this paper, we designed a BLyS antagonist peptide PT, based on the

Acknowledgments

This study was supported by National Sciences Fund (No. 30490240) and “973” Fund (No. 2003CB515508) of China.

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These authors contributed equally to this work.

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