Chapter 20. Cell Adhesion Integrins as Pharmaceutical Targets

The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

“…This work used conformationally constrained cyclic peptides bearing a similar small binding motif to inform the design of small molecule leads that had remarkably high selectivity for closely related integrin receptor subtypes (Engleman et al, 1996;Samanen, 1996;Samanen et al, 1996;Keenan et al, 1997).…”

A bioconjugate of Lys and Arg mimics biological activity of the Arg–Gly–Asp peptide sequence

“…BALB/c-3T3 cell adhesion and spreading on surface-immobilized dextran, RGD peptide-grafted dextran, and RGD peptide mimetic-grafted substrates. AAGPAHA and GRGDSP peptide were covalently immobilized on dextran-coated tissue culture plastic utilizing methods that we have developed for cell adhesion peptides [15][16][17]. All data are expressed as a percentage of control adhesion on uncoated tissue culture plastic.…”

“…Candidate reagents for biotherapeutic applications include monoclonal antibodies, RGD peptides, and peptidomimetics that block integrin function [15]. Peptidomimetics are of particular interest for therapeutic applications because they have low immunogenicity and are resistant to protease/peptidase-mediated degradation [15]. The major disadvantage to peptidomimetics is that they are typically difficult to synthesize requiring lengthy organic syntheses of precursors.…”

Vitronectin Receptor Antagonists: Purine-Based Peptidomimetics

“…[2e] In the development of organotin acylation catalysts, [2g,h, 3] we have established that they are so mild that various selective acylation reactions are feasible but their acidity is not strong enough to perform acylation of sterically hindered alcohols. In this context, we were intrigued to employ bismuth triflate Bi(OTf) 3 [4] since it had proved to be easy to handle due to its stability in the air and to be acidic enough to catalyze Friedel ± Crafts, [5] Diels ± Alder, [6] and ene reactions. [7] As shown in Table 1, Bi(OTf) 3 can promote the acetylation of primary, secondary, and tertiary alcohols in acetic anhydride at 25 8C [Eq.…”

“…The b 3 class of the integrin family, a IIb b 3 (GPIIb/IIIa or fibrinogen receptor) and a V b 3 (vitronectin receptor), has received special attention in recent drug research. [4,5] a IIb b 3 is prevalent on platelets and plays a role in thromboembolic disorders, [5] while a V b 3 is the dominant receptor for mediating the attachment of osteoclasts to bone during bone resorption [6,7] and has been implicated in tumor progression, angiogenesis, [5,8,9] and restenosis. [10] Many integrins, including a IIb b 3 and a V b 3 , interact with a common Arg-Gly-Asp (RGD) binding motif in their target proteins.…”