Design of superactive and selective integrin receptor antagonists containing the RGD sequence

Abstract

Integrins play a major role in cell-cell and cell-matrix interactions. The majority of the different types of integrins recognize the tripeptide sequence arginine-glycine-aspartic acid (RGD). To explore the spatial requirements of the pharmacophore for receptor selectivity and high activity, a new procedure, 'spatial screening', was used. The procedure is based on the experience that the conformation of small cyclic peptides is mainly determined by the chirality of the amino acids (and glycine or proline). For example, cyclic pentapeptides with one D and four L amino acids prefer a 13II'/~/conformation. The sequence RGDFV was shifted around this spatial I~II'/y template by synthesis of five peptides in which one of the amino acids was used in D-configuration. It turned out that cyclo(-RGDfV-) is a selective inhibitor for the %[33 integrin, which is strongly expressed in cancer cells. Systematic variations with different turn mimetics, retro-inverso structures, modified peptide bonds and sugar amino acids are discussed.

Origin of problems related to Staudinger reduction in carbopeptoid syntheses

“…β-Amino acid building blocks of cyclic skeleton are of special interest, as the ring structure puts constraint on the central θ-backbone torsional angle adjacent to ϕ and ψ and thus stabilizes specific secondary structural elements (Beke et al 2004). Recently, sugar amino acids (SAA), par-ticularly, fiveor six-membered cyclic amino sugar carbox-ylic acids, appeared as appropriate building blocks for car-bopeptoid foldamers (Herradón and Seebach 1989;Kessler et al 1995;Long et al 1999;Simone et al 2005;Sharma et al 2008Sharma et al , 2011Andreini et al 2009). Numerous furanoid and pyranoid carbohydrate analogs of trans-2-aminocyclo-pentane carboxylic acid (trans-ACPC) and trans-2-amino-cyclohexane carboxylic acid (trans-ACHC) were synthe-sized and built into homo-and heterooligomers to test their self-assembling abilities (Pandey et al 2011;Giri et al 2012;Risseeuw et al 2013).…”

Design, conformational studies and analysis of structure–function relationships of PTH (1–11) analogues: the essential role of Val in position 2

“…Introduction of conformational constraints, such as a-aminoisobutyric acid (Aib), into peptides, improves their activity and receptor binding selectivity (Hirschmann 1991;Gante 1994;Kessler et al 1995;Caporale et al 2010a). While alanine is easily accommodated in both folded and extended structures, theoretical and experimental studies performed on Aib (Kaul and Balaram 1999;Toniolo et al 2001;Torras et al 2008;Maity and König 2008) have highlighted its strong tendency to induce folded structures in the 3 10 -/a-helical region (u, w & ±60°, ±30°).…”

Lung Cancer

“…In particular, α v β 3 integrin is an excellent target for antiangiogenic interventions. Cyclic(Arg-Gly-Asp-D-Phe-Lys), also known as cyclic RGD, peptides have been developed to provide specific binding to α v β 3 integrins (Kessler et al 1995).…”