Design of Peptide Inhibitors That Bind the bZIP Domain of Epstein–Barr Virus Protein BZLF1 Citation

Designing proteins or peptides that bind native protein targets can aid the development of novel reagents and/or therapeutics. Rational design also tests our understanding of the principles underlying protein recognition. This paper describes several strategies used to design peptides to bind to the bZIP domain of the viral transcription factor BZLF1, which is encoded by the EpsteinBarr virus (EBV). BZLF1 regulates transition of EBV from a latent to a lytic state. It shares some properties in common with more-studied human bZIP transcription factors, but also includes novel structural elements that pose interesting challenges to inhibitor design. In designing peptides that bind to BZLF1 by forming a coiled-coil structure, we considered both affinity for BZLF1 and also undesired self-association, which can weaken the effectiveness of an inhibitor. Several designed peptides exhibited different degrees of target-binding affinity and self-association. Rationally engineered molecules were more potent inhibitors of DNA binding than a control peptide corresponding to the native BZLF1 dimerzation region itself. The most potent inhibitors included both positive and negative design elements and exploited interaction with the coiled-coil and basic DNA-binding regions of BZLF1.