The Constrained Amino Acid β‐Acc Confers Potency and Selectivity to Integrin Ligands

Abstract

Interactions between the extracellular matrix and membrane proteins are of importance for cell adhesion, tissue formation, and transmembrane signaling processes. Among cell adhesion molecules, integrins occupy a highly prominent position. Many integrins, among them a 5 b 1 and a V b 3 , recognize the tripeptide sequence -Arg-Gly-Asp-(RGD) in their ligands. The discovery of the role of the RGD sequence in cell-cell and cell-matrix interactions prompted the development of a broad variety of RGD peptides and peptidomimetics for potential therapeutic applications. Soluble derivatives of these compounds are able to competitively inhibit the interaction between an RGD-containing protein and its integrin counterpart, whereas immobilized RGD peptides support cell attachment, for example, to artificial implants.

Targeting αvβ3 Integrin: Design and Applications of Mono- and Multifunctional RGD-Based Peptides and Semipeptides

“…(8)) [36]. Unexpectedly, the conformation experimentally observed for (54) and (55) contained a II' turn with Gly at the i+1 position. Macrocycle (54) proved to be a moderate and selective antagonist of v 3 integrin, while the more flexible (55) was a potent v 3 inhibitor, albeit aspecific.…”

“…This was further confirmed by molecular modeling of (55) on v 3 integrin [23b], which revealed a H-bond between the guanidinium group of Arg214 and the carbonyl oxygen of the lactam. In docking (54), this productive interaction was missing, thus explaining its weaker activity in targeting v 3 integrin.…”

“…In the search for non peptidic RGD-containing cyclic systems based on II'/ arrangement with the -turn centred on Gly, classic dipeptide mimetics based on amino pyrrolidinone motifs were used by Kessler to graft macrocycles (54) and (55) (Fig. (8)) [36].…”

Stereoselective cis-Vinylcyclopropanation via a Gold(I)-Catalyzed Retro-Buchner Reaction under Mild Conditions

“…Considering the importance of sterically constrained β-amino acids, 40,41 we developed a simple access to such building blocks containing a cyclopropane ring. Thus, ozonolysis of 6a followed by reductive workup yielded cis -aldehyde 9a .…”

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

“…The building block b-Acc (cis-b-aminocyclopropanecarboxylic acid) is especially inflexible, due to the cyclopropane moiety. Each enantiomer of this amino acid has recently been introduced into a cyclic RGD pentapeptide [109]. The conformational restraint resulting from this introduction leads to an enhancement of the affinity and the selectivity of one of the diastereomers towards integrin a V b 3 (FiguRe 14).…”