Cyclopropane‐Based Peptidomimetics Mimicking Wide‐Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization

Abstract

Detailed conformational analyses of our previously reported cyclopropane-based peptidomimetics and conformational analysis-driven ligand optimization are described. Computational calculations and X-ray crystallography showed that the characteristic features of cyclopropane function effectively to constrain the molecular conformation in a three-dimensionally diverse manner. Subsequent principal component analysis revealed that the diversity covers the broad chemical space filled by peptide secondary structures in terms of both main-chain and side-chain conformations. Based on these analyses, a lead stereoisomer targeting melanocortin receptors was identified, and its potency and subtype selectivity were improved by further derivatization. The presented strategy is effective not only for designing non-peptidic ligands from a peptide ligand but also for the rational optimization of these ligands based on the plausible target-binding conformation without requiring the three- dimensional structural information of the target and its peptide ligands.

From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane

“…The orientation of the side chains of the central two residues (R i +1 and R i +2 ) may differ between each enantiomeric pair to increase the 3D structural diversity in terms of the side‐chain positioning. The 3D structures of these stereoisomers were corroborated by X‐ray crystallography of the simplified model compounds, in which both cyclopropylic strain and bisected conformational preference were observed in all stereoisomers …”

“…While vector descriptors may not be so easy to handle, principal component analysis could be an easier way to quantify the 3D structural diversity of the mimetics in the chemical space, describing the positional information of both Cα and Cβ atoms. Comparison of the eight stereoisomeric scaffolds (Figure ) with natural tetrapeptide motifs in an X‐ray structure database showed that the library of the designed eight mimetics covers a wide range of secondary structures of tetrapeptides, which consist of not only extended β‐strands and folded β‐turns, but also their intermediate conformations (Figure ) …”

“… Evaluating the 3D structural diversity of the designed peptidomimetics in comparison with the conformations of tetrapeptide motifs in a X‐ray structure database, PepX . a) The six carbon atoms, indicated by the magenta points, were selected to build the chemical space based on principal component analysis.…”

“…Biological evaluation of the synthesized mimetics demonstrated that mimetic 14 would be the lead targeting the human MCR subtype 4 (hMC4R). Further optimization resulted in the identification of more potent and selective ligand 15 at Step‐2 (Figure ) …”

A Macrocyclic Peptide Library with a Structurally Constrained Cyclopropane‐containing Building Block Leads to Thiol‐independent Inhibitors of Phosphoglycerate Mutase

“…Furthermore, the side chain orientation is largely restricted depending on the stereochemistry of the asymmetric carbon adjacent to cyclopropane by the cyclopropylic strain. [39][40] Here we report construction of a cyclopropanecontaining macrocyclic peptide library aiming at reducing the probability of the formation of lariat-peptide species and its application for in vitro selection against a phosphoglycerate mutase, demonstrating the development of macrocyclic peptides inhibiting the enzyme with a different mode of action from the previously reported peptides. [37] We designed a cyclopropane-containing γ-amino acid (γCp), which had a cis-configurated backbone and an anti-oriented isobutyl group [41] as a sidechain.…”