Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design

J Med Chem. 2016 Dec 22;59(24):10865-10890. doi: 10.1021/acs.jmedchem.6b01029. Epub 2016 Oct 12.


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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Aromatic / chemistry
  • Amino Acids, Aromatic / pharmacology*
  • Animals
  • Cyclization
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzymes / metabolism*
  • Humans
  • Molecular Conformation
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Amino Acids, Aromatic
  • Enzyme Inhibitors
  • Enzymes
  • Peptides
  • Peptidomimetics
  • Receptors, G-Protein-Coupled