title: Structure-Activity Studies on Antiproliferative Factor (APF) Glycooctapeptide Derivatives.
abstract: Antiproliferative factor (APF), a sialylated glycopeptide secreted by explanted bladder epithelial cells from interstitial cystitis/painful bladder syndrome (IC/PBS) patients, and its unsialylated analogue (as-APF) significantly decrease proliferation of bladder epithelial cells and/or certain carcinoma cell lines in vitro. We recently reported a structure-activity relationship profile for the peptide portion of as-APF and revealed that truncation of the C-terminal alanine did not significantly affect antiproliferative activity. To better understand the structural basis for the maintenance of activity of this truncated eight amino acid as-APF (as-APF8), we synthesized several amino acid-substituted derivatives and studied their ability to inhibit bladder epithelial cell proliferation in vitro as well as their solution conformations by CD and NMR spectroscopy. While single amino acid changes to as-APF8 often strongly reduced activity, full potency was retained when the trivaline tail was replaced with three alanines. The Ala(6-8) derivative 9 is the simplest, fully potent APF analogue synthesized to date.
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kaczmarek
authors.affiliation: Molecular Aspects of Drug Design Section, Structural Biophysics Laboratory.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tocci
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201 ; Research Service, Veterans Administration Maryland Health Care System, Baltimore, Maryland 21201.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Keay
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program.
authors.forename: Kristie M
authors.initials: KM
authors.lastname: Adams
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Chen-Ou
authors.initials: CO
authors.lastname: Zhang
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Kristopher R
authors.initials: KR
authors.lastname: Koch
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: David
authors.initials: D
authors.lastname: Grkovic
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Li
authors.initials: L
authors.lastname: Guo
authors.affiliation: Molecular Aspects of Drug Design Section, Structural Biophysics Laboratory.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Michejda
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Barchi
keywords: Interstitial cystitis/painful bladder syndrome; antiproliferative; glycopeptide; hydrophobicity; peptide conformation