title: Design of peptide inhibitors that bind the bZIP domain of Epstein-Barr virus protein BZLF1.
abstract: 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 article describes several strategies used to design peptides that bind to the basic region leucine zipper (bZIP) domain of the viral transcription factor BZLF1, which is encoded by the Epstein-Barr virus. BZLF1 regulates the transition of the Epstein-Barr virus from a latent state to a lytic state. It shares some properties in common with the 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 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 dimerization 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.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Building 68-622, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: T Scott
authors.initials: TS
authors.lastname: Chen
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Reinke
authors.forename: Amy E
authors.initials: AE
authors.lastname: Keating
mesh_terms: D000595:Amino Acid Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002942:Circular Dichroism; D004247:DNA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015195:Drug Design; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D011487:Protein Conformation; D055503:Protein Multimerization; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D050976:Basic-Leucine Zipper Transcription Factors; D010446:Peptide Fragments; D015534:Trans-Activators; D004247:DNA