Oligo(N‐methylalanine) as a Peptide‐Based Molecular Scaffold with a Minimal Structure and High Density of Functionalizable Sites

Abstract

Functionalizable synthetic molecules with nanometer sizes and defined shapes in water are useful as molecular scaffolds to mimic the functions of biomacromolecules and develop chemical tools for manipulating biomacromolecules. Herein, we propose oligo(N-methylalanine) (oligo-NMA) as a peptide-based molecular scaffold with a minimal structure and a high density of functionalizable sites. Oligo-NMA forms a defined shape in water without hydrogen-bonding networks or ring constraints, which enables the molecule to act as a scaffold with minimal atomic composition. Furthermore, functional groups can be readily introduced on the nitrogens and α-carbons of oligo-NMA. Computational and NMR spectroscopic analysis suggested that the backbone structure of oligo-NMA is not largely affected by functionalization. Moreover, the usefulness of oligo-NMA was demonstrated by the design of protein ligands. The ease of synthesis, minimal structure, and high functionalization flexibility makes oligo-NMA a useful scaffold for chemical and biological applications.

A high-resolution structural characterization and physicochemical study of how a peptoid binds to an oncoprotein MDM2

“…This is consistent with the previous observations that modifications to these N -substituents largely changed the binding affinity. 6,10,11 The buried surface area of the complex is 996 Å 2 . It is smaller than that of the peptidic binder, p53-TAD (PDB ID , 13 1477 Å 2 ) but larger than that of the small molecule binder, Nutlin-3a (PDB ID , 14 825 Å 2 ).…”

“…(C) Hot-spot residues of p53-TAD, namely Phe19, Trp23, and Leu26 (PDB ID 1YCR), 13 the design flow of MDM2-binding peptoids, and chemical structures of peptoids 1 and 2 that bear functional N-substituents (orange) corresponding to the three hot-spot residues of p53-TAD. 6,10,11 S1 †). Although there have been reports about crystal structures of peptides containing a peptoid residue or peptoid monomers bound to a protein, to the best of our knowledge, this is the rst high-resolution structure of a peptoid oligomer bound to a protein.…”

“…Using this NSA-type peptoid as a scaffold, we developed the MDM2-binding peptoid by displaying three functional groups on amide nitrogens of an NSAtype peptoid, mimicking three hot-spot residues of p53, MDM2binding protein. 6,10 Furthermore, by optimizing three Nsubstituents, NSA-type peptoid 1, which has a high binding affinity to MDM2, was successfully obtained (Fig. 1C).…”

Residue-based program of a β-peptoid twisted strand shape via a cyclopentane constraint

“…The stable and predictable three-dimensional structure of oligo-NSA is beneficial for designing functional molecules like protein ligands. 28,29 Expansion of the repertoire of such preorganized monomers could contribute to the preparation of diverse peptoid shapes of high stability and predictability.…”

Quantitative and Nondestructive Colorimetric Amine Detection Method for the Solid-Phase Peptide Synthesis as an Alternative to the Kaiser Test

“…Solid-phase peptide synthesis (SPPS) is a widely used method for chemical peptide synthesis. , To monitor the completion of peptide coupling reactions, the Kaiser test based on the ninhydrin reaction has been utilized to visualize unreacted free amino groups on the resin (Figure a) . However, the Kaiser test has several disadvantages: (1) some amino acids, such as proline , and N -alkylated , and α,α-disubstituted , α-amino acids, are not detectable; (2) a small amount of resin must be aliquoted from a peptide synthesis vessel for the test; (3) toxic KCN is necessary as a reductant; (4) quantitative analysis is impractical; etc. Aliquoting resin is a common drawback for reaction-based amine detection methods. , To address these issues, nondestructive one-pot amine detection methods have been developed .…”