A PARADIGM FOR DRUG DISCOVERY USING A CONFORMATION FROM THE CRYSTAL-STRUCTURE OF A PRESENTATION SCAFFOLD

We describe a structural validation of the use of presentation scaffolds for control and elucidation of bioactive conformations of peptides. The protein REI-RGD34- produced by inserting the sequence RIPRGDMP into the CDR1 loop region of the immunoglobulin V-L domain REI-strongly inhibits fibrinogen binding to the integrins alpha (IIb)beta(3) and alpha(V) beta(3). In the X-ray crystal structure of this protein at 2.4 Angstrom resolution, the RGD-containing loop exhibits defined electron density that is consistent with models for the bioactive conformations of ligands of these receptors based on previous small-molecule studies. Furthermore, a search of a small- molecule database with conformational information derived from the structure of REI-RGD34 identified constrained peptides and peptidomimetics known to be antagonists of the platelet receptor alpha(IIb)beta(3).