jm6b01029_si_001.pdf (293.38 kB)
Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design
journal contributionposted on 2016-10-03, 00:00 authored by Olivier Van der Poorten, Astrid Knuhtsen, Daniel Sejer Pedersen, Steven Ballet, Dirk Tourwé
Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute the peptide pharmacophore is equally important. Control of χ-space utilizes conformationally constrained amino acids that favor, disfavor, or exclude the gauche (−), the gauche (+), or the trans conformation. In this review we focus on cyclic aromatic amino acids in which the side chain is connected to the peptide backbone to provide control of χ1- and χ2-space. The manifold applications for cyclized analogues of the aromatic amino acids Phe, Tyr, Trp, and His within peptide medicinal chemistry are showcased herein with examples of enzyme inhibitors and ligands for G protein-coupled receptors.
acids PhefocusGreat ToolsPeptidomimetic Design Constrainingχ- spacemanifold applicationstrans conformationincrease potencycyclized analoguesbackbone dihedral anglespeptide pharmacophorepeptide backboneside chainenzyme inhibitorsLocal Constraintsχ 1χ 2side Chain Cyclized Aromatic Amino AcidsG protein-coupled receptors