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Discovery and investigation of lead compounds as binders to the Extra‐Domain B of the angiogenesis marker, fibronectin
Author(s) -
Scheuermann Jörg,
Volonterio Alessandro,
Zerbe Oliver,
Zanda Matteo,
Neri Dario
Publication year - 2003
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10161
Subject(s) - angiogenesis , chemistry , fibronectin , heteronuclear molecule , binding domain , amino acid , moiety , biochemistry , stereochemistry , binding site , nuclear magnetic resonance spectroscopy , biology , cancer research , extracellular matrix
Angiogenesis, the growth of new blood vessels from preexisting vessels, is a rare event in the adult (except in the case of the female reproductive cycle), but is a characteristic feature of diseases such as cancer, blinding ocular disorders (e.g., retinopathies), and rheumatoid arthritis. The ED‐B domain of fibronectin, a domain of 91 amino acids, inserted by a mechanism of alternative splicing of the primary transcript into the fibronectin molecule, is a high‐quality marker of angiogenesis and a target for molecular intervention, characterized by a high number of acidic residues on its surface, as well as some solvent‐exposed hydrophobic residues. A library of 113 low molecular‐weight organic compounds, containing both an aromatic moiety and at least one positive charge, was screened for binding to the ED‐B domain, using two‐dimensional heteronuclear NMR spectroscopy. One lead compound, 2,2‐diphenylethylamine, was found that binds specifically to the ED‐B domain, albeit with a dissociation constant in the millimolar range. Chemical modification of this scaffold revealed structural determinants required for binding, as well as amino acid residues in the ED‐B domain responsible for the interaction. The results presented represent the basis for the development of high‐affinity, low molecular‐weight binders by using a linked‐fragment approach or elongating the scaffold by means of combinatorial chemistry. Drug Dev. Res. 58:268–282, 2003. © 2003 Wiley‐Liss, Inc.