Peptidomimetics - Antagonists of the Fibrinogen Receptors: Molecular Design, Structures, Properties and Therapeutic Applications

Abstract

The platelet aggregation is a crucial step in a pathophisiology of thromboses, leading to development of cardio-vascular diseases (myocardial infarction, transient ischemic attacks, strokes, etc.). The final step in the aggregation is the binding of fibrinogen to receptor - glycoprotein IIb/IIIa (GP IIb/IIIa) on the surface of activated platelets. In recent years the increasing attention is paid to the role of fibrinogen antagonists in the prevention of thrombosis. The search for these compounds is based on the molecular design of structures mimicking some fragment of RGD (Arg-Gly-Asp) sequence, responsible for the binding of fibrinogen to GP IIb/IIIa. Up to now, a large number of potent and selective GP IIb/IIIa antagonists, including non-peptide inhibitors are identified (derivatives of benzodiazepines, aminobenzamidinosuccinyles, isoxazolines, isoquinolines). The modification of natural peptide structures for obtaining of more active and selective fibrinogen receptor antagonists is realized in several ways: substitution of main pharmacophores of RGD sequence; cyclization of RGD-containing peptides; design of conformationally constrained peptidomimetics. For the treatment of chronic cardio-vascular diseases, the clinic needs high orally active RGD-peptidomimetics. This task is realized by obtaining of prodrugs on the base of the most potent RGD-mimetics. In our laboratory the molecular design and synthesis of non-peptide fibrinogen receptor antagonists were carried out. The series of RGD-mimetics on the basis of 4-oxo-(piperazine-1-yl)butyric acid as Arg-mimetic and beta-aryl-beta-alanines as Asp-Phe-mimetics were synthesized. Obtained RGD-mimetics showed a high antiaggregatory activity in vitro experiments with IC(50)values of 10(-7) - 10(-9) M.

Identification of a Small Peptide That Inhibits PCSK9 Protein Binding to the Low Density Lipoprotein Receptor

“…The small size of the peptide (13 residues) serves to identify a focused epitope on PCSK9 and highlights key interactions that ligands must make to obtain a high binding energy. Although peptides are not usually considered as orally bioavailable drug candidates, several examples exist in the literature where peptides have served as the starting point for the successful development of small molecule drugs that exhibit oral bioavailability (44,45,54). Conceivably, Pep2-8 could provide such a steppingstone to go from protein to small molecule drug antagonists of the LDL receptor-PCSK9 interaction.…”

Reversal of Regioselectivity and Enhancement of Rates of Nitrile Oxide Cycloadditions through Transient Attachment of Dipolarophiles to Cyclodextrins

“…This effectively reverses the regioselectivity and substantially enhances the rates of the cycloadditions, thus providing ready access to 4-substituted isoxazolines with various potential applications in chemistry [84,86,87] and pharmacy. [88][89][90] Experimental Section…”

Untitled

“…In the process of blood clotting and platelet aggregation, the last step involves the binding of fibrinogen to receptorglycoprotein IIb / IIIa (GP IIb / IIIa) on the surface of activated platelets. This mechanism is being targeted in recent years to develop fibrinogen antagonists for application in preventing Thrombosis 74 . Fragments of RGD (Arg-Gly-Asp) sequence have been mimicked which are responsible for the binding of Fibrinogen to GP IIb/IIIa.…”