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

Abstract

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 χ- and χ-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.

Development of potent and proteolytically stable human neuromedin U receptor agonists

“…However, when Phe is replaced by 7-OH-Tic, a decrease in affinity for NMUR1 was found. This could be explained by the fact that an unfavorable conformational constraint is imposed, and hence that the side chain is forced in a less favorable position for binding to the NMURs [34].…”

Copper‐Free Solid‐Phase Synthesis of Triazolo[1,5‐a][1,4]diazepin‐6‐ones

“…Additionally, the developed protocols were successfully applied to solid‐phase synthesis of triazolodiazepinone‐based peptidomimetic which allows for the simple synthesis of long peptides with constrained histidine mimicking effects using convenient solid‐phase peptide synthesis. With respect to the high potential of constrained peptidomimetics leading to the peptide analogues with an increased potency, efficacy and selectivity, [26] the reported protocols offer a simple tool for the production of novel drug‐like molecules.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Besides, a single compound can show more than one conformation, so, based on the available threedimensional structures, a strategy of constraining the conformation of flexible molecules (eg, forming a macrocycle between two solvent-exposed substituent positions of a given binder) is well-established to improve potency, selectivity, and PKs or absorption, distribution, metabolism, and excretion (ADME)-related properties (eg, metabolic stability), while having a minimal effect on the therapeutically relevant binding interaction. 69,80,81 Indeed, this approach has yielded new inhibitors with improved PK properties as well as increased enzyme affinity, as exemplified by a wide range of macrocyclic antiviral agents, such as hepatitis C virus (HCV) NS5B Figure 18). 93,94 For example, taking peptidomimetic HIV-1 gp120 antagonist 121 as a lead compound, cyclic peptide triazole (cPT) derivatives were obtained via cyclization of two solvent-exposed substituent positions, thereby locking the molecule in an active conformation.…”