BAFF antagonists designed by computer-aided drug design inhibited the interaction of BAFF with its receptors

Abstract BAFF is a critical factor for B cell maturation and survival, and its overexpression is involved in pathogenesis of autoimmune diseases. As blockade of BAFF activity significantly improves the symptoms of autoimmune diseases such as SLE and RA, BAFF is a promising therapeutic target for treating these diseases. Currently, most BAFF antagonists are antibodies against BAFF or soluble BAFF receptor-IgG1 Fc fusion proteins. Small molecules such as peptides as antagonists to block the biological activity of cytokines have been investigated intensively. Based on the crystal structures of the protein–protein complexes, protein mimics can be designed as antagonists with computer-aided drug design (CADD) to block the cytokine-receptor interactions. Since the crystal structures of BAFF and its receptors are known, we designed BAFF antagonist peptides with CADD. The peptides could inhibit the binding of BAFF with its receptors BCMA, TACI and BR3. In addition, BAFF-binding peptides originated from CADD were compared to the peptide selected from the phage display library. Both kinds of peptides could inhibit the binding of BAFF to its receptors, a peptide from the phage display library showed two-fold inhibition effect on BAFF binding to its receptors. 3-copy vs 1-copy of peptides were also studied and the results indicated that increasing the copy numbers of peptides in peptide-Fc fusion proteins did not significantly enhance the bioactivities of the peptides. Therefore, BAFF antagonist peptides designed by CADD could bind to BAFF in a dose-dependent manner and inhibit BAFF biological activity significantly, which might be potential agents for autoimmune disease therapies.