Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors. An integrated strategy for the development of new antiangiogenic compounds (Articolo in rivista)

Type
Label
  • Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors. An integrated strategy for the development of new antiangiogenic compounds (Articolo in rivista) (literal)
Anno
  • 2010-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1074/jbc.M109.085605 (literal)
Alternative label
  • Colombo G.; Margosio B.; Ragona L.; Neves M.; Bonifacio S.; Annis D.S.; Stravalaci M.; Tomaselli S.; Giavazzi R.; Rusnati M.; Presta M.; Zetta L.; Mosher D.F.; Ribatti D.; Gobbi M.; Taraboletti G. (2010)
    Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors. An integrated strategy for the development of new antiangiogenic compounds
    in The Journal of biological chemistry (Print)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Colombo G.; Margosio B.; Ragona L.; Neves M.; Bonifacio S.; Annis D.S.; Stravalaci M.; Tomaselli S.; Giavazzi R.; Rusnati M.; Presta M.; Zetta L.; Mosher D.F.; Ribatti D.; Gobbi M.; Taraboletti G. (literal)
Pagina inizio
  • 8733 (literal)
Pagina fine
  • 8742 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 285 (literal)
Rivista
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Colombo G-ICRM-Milano, Margosio B- Istituto Mario Negri-Bergamo, Ragona L. - Ismac-Milano, Neves, M- ICRM-Milano Bonifacio S, Istituto Mario Negri-Bergamo Annis DS- Istituto Mario Negri-Bergamo, Stravalaci M, Istituto Mario Negri-Milano - Tomaselli S. - Ismac-Milano, Giavazzi, R- Istituto Mario Negri-Milano - Rusnati, M- Università di Brescia -Presta M. – Università di Brescia - Zetta L. - Ismac-Milano, Mosher DF, University of Wisconsin, Madison, WI -Ribatti D-University of Bari- Gobbi M, Istituto Mario Negri-Milano -Taraboletti G, Istituto Mario Negri-Bergamo (literal)
Titolo
  • Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors. An integrated strategy for the development of new antiangiogenic compounds (literal)
Abstract
  • Endogenous inhibitors of angiogenesis, such as thrombospondin-1 (TSP-1), are promising sources of therapeutic agents to treat angiogenesis-driven diseases, including cancer. TSP-1 regulates angiogenesis through different mechanisms, including binding and sequestration of the angiogenic factor fibroblast growth factor-2 (FGF-2), through a site located in the calcium binding type III repeats. We hypothesized that the FGF-2 binding sequence of TSP-1 might serve as a template for the development of inhibitors of angiogenesis. Using a peptide array approach followed by binding assays with synthetic peptides and recombinant proteins, we identified a FGF-2 binding sequence of TSP-1 in the 15-mer sequence DDDDDNDKIPD-DRDN. Molecular dynamics simulations, taking the full flexibility of the ligand and receptor into account, and nuclear magnetic resonance identified the relevant residues and conformational determinants for the peptide-FGF interaction. This information was translated into a pharmacophore model used to screen the NCI2003 small molecule databases, leading to the identification of three small molecules that bound FGF-2 with affinity in the submicromolar range. The lead compounds inhibited FGF-2-induced endothelial cell proliferation in vitro and affected angiogenesis induced by FGF-2 in the chicken chorioallantoic membrane assay. These small molecules, therefore, represent promising leads for the development of antiangiogenic agents. Altogether, this study demonstrates that new biological insights obtained by integrated multidisciplinary approaches can be used to develop small molecule mimics of endogenous proteins as therapeutic agents. (literal)
Prodotto di
Autore CNR

Incoming links:


Autore CNR di
Prodotto
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#rivistaDi
data.CNR.it