title: Potential C-terminal-domain inhibitors of heat shock protein 90 derived from a C-terminal peptide helix.
abstract: Hsp90 is a molecular chaperone implicated in many diseases including cancer and neurodegenerative disease. Most inhibitors target the ATPase site in Hsp90's N-terminal domain, with relatively few inhibitors of other domains reported to date. Here, we show that peptides derived from a short helix at the C-terminus of Hsp90 show micromolar activity as Hsp90 inhibitors in vitro. These inhibitors do not block the N-terminal domain's ATP-binding site, and thus are likely to bind at the C-terminal domain. Substitutions and helix stapling were applied to demonstrate structure-activity relationships and improve activity. These helical peptides will help guide the design of a new class of inhibitors of Hsp90's C-terminal domain.
authors.affiliation: Department of Chemistry, Tufts University, 62 Talbot Ave, Medford, MA 02155, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Gavenonis
authors.affiliation: Department of Chemistry, Tufts University, 62 Talbot Ave, Medford, MA 02155, United States.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Jonas
authors.affiliation: Department of Chemistry, Tufts University, 62 Talbot Ave, Medford, MA 02155, United States. Electronic address: joshua.kritzer@tufts.edu.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Kritzer
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D010455:Peptides; D000255:Adenosine Triphosphate
keywords: Hsp90; Molecular chaperones; Peptides; Protein–protein interactions; Stapled helices