title: Identification of inhibitors against interaction between pro-inflammatory sPLA2-IIA protein and integrin αvβ3.
abstract: Increased concentrations of secreted phospholipase A2 type IIA (sPLA2-IIA), have been found in the synovial fluid of patients with rheumatoid arthritis. It has been shown that sPLA2-IIA specifically binds to integrin αvβ3, and initiates a signaling pathway that leads to cell proliferation and inflammation. Therefore, the interaction between integrin and sPLA2-IIA could be a potential therapeutic target for the treatment of proliferation or inflammation-related diseases. Two one-bead-one-compound peptide libraries were constructed and screened, and seven target hits were identified. Herein we report the identification, synthesis, and biological testing of two pyrazolylthiazole-tethered peptide hits and their analogs. Biological assays showed that these compounds were able to suppress the sPLA2-IIA-integrin interaction and sPLA2-IIA-induced migration of monocytic cells and that the blockade of the sPLA2-IIA-integrin binding was specific to sPLA2-IIA and not to the integrin.
authors.affiliation: Department of Chemistry, University of California, Davis, CA 95616, United States.
authors.forename: Long
authors.initials: L
authors.lastname: Ye
authors.forename: Tiffany
authors.initials: T
authors.lastname: Dickerson
authors.forename: Handeep
authors.initials: H
authors.lastname: Kaur
authors.forename: Yoko K
authors.initials: YK
authors.lastname: Takada
authors.forename: Masaaki
authors.initials: M
authors.lastname: Fujita
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Liu
authors.forename: John M
authors.initials: JM
authors.lastname: Knapp
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.forename: Neil E
authors.initials: NE
authors.lastname: Schore
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D062105:Molecular Docking Simulation; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry
chemical_list: D039302:Integrin alphaVbeta3; D019151:Peptide Library; D010455:Peptides; D013844:Thiazoles; D054501:Group II Phospholipases A2