Peptoid-based reprogrammable template for cell-permeable inhibitors of protein–protein interactions

Fukuda, Yasuhiro; Yokomine, Marin; Kuroda, Daisuke; Tsumoto, Kouhei; Morimoto, Jumpei; Sando, Shinsuke

doi:10.1039/d1sc01560e

“…As a result, compound 9 showed the highest inhibitory activity among the tested derivatives (the data for weaker derivatives are not shown), inhibiting the interaction between PMI and MDM2 at K i =0.70 μM (Figure 5b, S10). The inhibitory activity was comparable to that of the N ‐functionalized oligo‐NMA‐based MDM2 inhibitor that we previously reported [23] …”

Section: Resultssupporting

confidence: 84%

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

Yokomine

¹

,

Morimoto

²

,

Fukuda

³

et al. 2022

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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.

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“…The inhibitory activity was comparable to that of the N-functionalized oligo-NMA-based MDM2 inhibitor that we previously reported. [23] These results demonstrated that many candidate structures for protein ligands can be generated by recruiting oligo-NMAs as scaffolds and functionalizing the scaffolds at the α-carbon and amide nitrogen.…”

Section: Methodsmentioning

confidence: 84%

“…Although the functional groups introduced in this study are limited to several aliphatic and aromatic groups, many other functional groups such as amine, carboxylic acid, and alcohol can be introduced as partially demonstrated in our previous studies. [19,23] Although the shape of the oligo-NMA scaffolds is limited to the extended shape using the homochiral oligo-NMAs consisting of only either N-methyl-L-alanine or N-methyl-D-alanine as shown in this study, various other shapes can be potentially realized using heterochiral oligo-NMAs consisting of a combination of N-methyl-L-alanine and N-methyl-D-alanine. Such an effort on increasing the shape diversity is underway in our laboratory.…”

Section: Discussionmentioning

confidence: 96%

“…The ten designed peptides were synthesized using the submonomer synthetic method that we previously reported (Figure 5a). [19,23] C α -substituents were introduced by coupling Fmoc-amino acids or Fmoc-N-methyl amino acids, and Nsubstituents were introduced by reductive amination or the Fukuyama-Mitsunobu reaction. This method allows the facile synthesis of functionalized oligo-NMAs with diverse N/C α -substituents.…”

Section: In Silico Design Of Mdm2 Ligands Using Oligo-nma As a Scaffoldmentioning

confidence: 99%

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

Yokomine

¹

,

Morimoto

²

,

Fukuda

³

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

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“…In addition, Morimoto and Sando's group recently succeeded in preparing peptoid foldamers with oligo-N-substituted alanine (oligoNSA) that stably form specific conformations by introducing asymmetric substituents on the peptoid backbone [104]. Furthermore, this oligoNSA is a useful framework for intracellular PPI inhibitors [113]. Foldamers with combinations of α-amino acids and peptoid monomers are also potent PPI inhibitors.…”

Section: Peptoidsmentioning

confidence: 99%

Helical Foldamers and Stapled Peptides as New Modalities in Drug Discovery: Modulators of Protein-Protein Interactions

Tsuchiya

¹

,

Kurohara

²

,

Fukuhara

³

et al. 2022

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A “foldamer” is an artificial oligomeric molecule with a regular secondary or tertiary structure consisting of various building blocks. A “stapled peptide” is a peptide with stabilized secondary structures, in particular, helical structures by intramolecular covalent side-chain cross-linking. Helical foldamers and stapled peptides are potential drug candidates that can target protein-protein interactions because they enable multipoint molecular recognition, which is difficult to achieve with low-molecular-weight compounds. This mini-review describes a variety of peptide-based foldamers and stapled peptides with a view to their applications in drug discovery, including our recent progress.

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Peptoid-based reprogrammable template for cell-permeable inhibitors of protein–protein interactions

Abstract: The development of inhibitors of intracellular protein–protein interactions (PPIs) is of great significance for drug discovery, but the generation of a cell-permeable molecule with high affinity to protein is challenging....

Cited by 13 publications

References 48 publications

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

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

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

Helical Foldamers and Stapled Peptides as New Modalities in Drug Discovery: Modulators of Protein-Protein Interactions

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