title: Structure-based optimization of a peptidyl inhibitor against calcineurin-nuclear factor of activated T cell (NFAT) interaction.
abstract: Calcineurin inhibitors such as cyclosporine A and FK506 are effective immunosuppressants but produce severe side effects. Rational modification of a previously reported peptide inhibitor, GPHPVIVITGPHEE (KD ∼ 500 nM), by replacing the two valine residues with tert-leucine and the C-terminal proline with a cis-proline analogue, gave an improved inhibitor ZIZIT-cisPro, which binds to calcineurin with a KD value of 2.6 nM and is more resistant to proteolysis.
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Qian
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Dougherty
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Shameema
authors.initials: S
authors.lastname: Oottikkal
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Hogan
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hadad
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004355:Drug Stability; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010455:Peptides / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; D010455:Peptides; D019703:Calcineurin