Controlling Cyclopeptide Backbone Conformation with β/α‐Hybrid Peptide–Heterocycle Scaffolds

Abstract

Cyclopeptides (CPs) have been recognized as excellent templates for the rational design of biologically active compounds. However, in the absence of constraining elements, even the small cyclotetrapeptides (CTPs) and cyclopentapeptides (CPPs) may show conformational heterogeneity, with the occurrence of mixtures of cis/trans‐peptide bonds. In this paper, we discuss the synthesis of CTP and CPP model compounds containing 5‐aminomethyloxazolidine‐2,4‐dione (Amo)‐dipeptide scaffolds, which combine a β/α‐hybrid dipeptide structure & a Freidinger lactam‐like heterocycle. Depending on the stereochemistry, the dipeptide scaffolds were shown to efficiently promote well‐defined turn structures within the CP sequences, by taking advantage of the particular local constraints, and by establishing extra intramolecular hydrogen‐bonding interactions.

Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds

“…We believe that the cyclization is the crucial step lowering the yields in our case. Conformational preorganization is in general essential for cyclization, and the presence of elements able to impart a turn to the linear peptide chains (especially if located in the central region of the polypeptide), greatly improves the yields [ 34 , 35 ]. In our case this preorganization is missing and the final yields are only satisfying.…”

“…In addition, their incorporation into peptides of pharmacological interest was sometimes advantageous in terms of biological activity, metabolic stability, and conformational characteristics. In particular, β-amino acids stabilize distinct overall conformations of cyclopeptides and they act as γ-turn mimetics: [ 34 , 35 ], if a single β-amino acid is incorporated into a cyclic pentapeptide, it preferably occupies the central position of a γ-turn. These conformational preferences were thoroughly investigated in the field of RGD-cyclopeptides by the introduction of β-aminocyclopropane carboxylic acids (β-ACCs) [ 36 ], which are among the most restricted β-alanine derivatives, and whose rigidity is conferred by the small-sized ring closure.…”

DS‐70, a novel and potent α4 integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs

“…The linear peptides BIO1211 and DS‐70 were prepared by solid phase peptide synthesis on a Wang resin, using Fmoc‐protected amino acids, under microwave irradiation conditions optimized by us (Gentilucci et al, ). The removal of Fmoc group was performed by treatment with piperidine in DMF, under microwave irradiation for 2 min.…”

Selective detection of α4β1 integrin (VLA‐4)‐expressing cells using peptide‐functionalized nanostructured materials mimicking endothelial surfaces adjacent to inflammatory sites

“…The peptides were prepared in solid phase on a Wang resin using fluorenylmethyloxycarbonyl (Fmoc)‐protected amino acids, according to a recently optimized MW‐assisted procedure . Residues with reactive side chains were protected with acido‐labile groups, that is, Fmoc‐Asp(O t Bu)‐OH, Fmoc‐Cys(Trt)‐OH (Trt = triphenylmethyl), Fmoc‐Ser( t Bu)‐OH, while Gln was introduced as Ac‐Gln‐OH.…”