Design and synthesis of conformationally constrained amino acids as versatile scaffolds and peptide mimetics

Peptidomimetics, a synthetic tool of drug discovery

“…Indolizidine-2-one and -9-one amino acids, representing 6,5 and 5,6 scaffolds, were used as β-turn scans to explore the conformational requirements for activity of analogues of Calcitonin-gene related peptide (CGRP) antagonist, together with aza-aminoacid scans [32]. The importance of a type II' β-turn centered at Gly 33 [27][28][29][30][31][32][33][34][35][36][37] has been illustrated by increased antagonistic potency of the azaGly 33 and indolizidine-2-one amino acid [33][34] analogues. In addition, the improved metabolic stability and longer duration of action qualifies those scans to be another peptidomimetic research tool.…”

“…In addition, the improved metabolic stability and longer duration of action qualifies those scans to be another peptidomimetic research tool. The older reviews [33,34] related to azabicycloalkane scaffolds provide a general overview of synthetic and conformational possibilities.…”

Structural characterization of a β-turn mimic within a protein–protein interface

“…The synthesis of conformationally constrained β-turn mimics with native-like side chains is hampered by the expense of designing an oligocyclic scaffold that is adequately protected for solid-phase peptide synthesis (13). Polyhydroxylated dipeptides with diversified stereochemistries can be obtained from uronolactones in a straightforward way (14,15).…”

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues

“…Bicyclic dipeptide mimetics have been designed and synthesized in this area for over ten years. 9,10 Previous studies have found that a [5,5]-bicyclic mimetic could approximate a type II ␤-turn, 11,12 a [6,5]-bicyclic could closely mimic a type IIЈ ␤-turn, 12,13 while a [7,5]-bicyclic structure can lead to different reverse turn structures depending on the chirality. 14 However, introduction of these bicyclic scaffolds into peptides has been quite limited because multistep syntheses were required, but were difficult to accomplish.…”