Advancing protein-protein interaction inhibitor design using minimal self-standing peptide mimetics based on an oligo(<em>N</em>-methylalanine) framework — ASN Events
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  2. SESSION 13: Foldamers and nanotechnology
  3. Advancing protein-protein interaction inhibitor design using minimal self-standing peptide mimetics based on an oligo(N-methylalanine) framework

Advancing protein-protein interaction inhibitor design using minimal self-standing peptide mimetics based on an oligo(N-methylalanine) framework (#73)

Shinsuke Sando 1 , Jumpei Morimoto 1 , Marin Yokomine 1
  1. The University of Tokyo, Tokyo, Japan

Protein-protein interactions (PPI) play crucial roles in various biological processes, which makes them attractive targets for therapeutic intervention. Despite growing interest in developing peptide mimetics as PPI inhibitors, a universal molecular framework remains elusive. Our research proposes the utilization of N-substituted peptides as a versatile framework for the design of self-standing peptide mimetics [1-5].

Oligo(N-methylalanine) (oligo-NMA) forms a distinctive extended shape in aqueous environments due to the pseudo-allylic strain per residue [1]. We employed oligo-NMA as a molecular scaffold to construct effective inhibitors of the MDM2-p53 interaction [1,3]. The MDM2-p53 interaction is mainly governed by three “hot spot” amino acid residues. By displaying these amino acids' side-chain structures on the oligo-NMA scaffold, we could design an inhibitor of the MDM2-p53 interaction rationally. Another advantage of the oligo-NMA scaffold is its high cell membrane permeability. Consequently, we also showed that the designed inhibitors function intracellularly [4]. Recently, we have demonstrated that by manipulating the L/D-chirality of alanine, the oligo-NMA, called heterochiral oligo-NMA, can adopt a wide array of structures beyond the aforementioned extended conformation [5]. Our research showcases the potential of oligo-NMA as a versatile platform for designing PPI inhibitors.

In this presentation, I will discuss the innovative use of oligo-NMA in developing PPI inhibitors. We are particularly excited to share the co-crystal structure of the oligo-NMA-based inhibitor with its target protein. This provides unprecedented insights into how the peptoid inhibitor interacts with the protein at the molecular level.

References:

  1. Morimoto and Sando et al. J. Am. Chem. Soc. 2019, 141, 14612-14623.
  2. Morimoto and Sando et al. J. Am. Chem. Soc. 2020, 142, 2277–2284.
  3. Morimoto and Sando et al. Angew. Chem. Int. Ed. 2022, 61, e202200119.
  4. Morimoto and Sando et al. Chem. Sci. 2021, 12, 13292–13300.
  5. Morimoto and Sando et al. ChemRxiv 2023, DOI: 10.26434/chemrxiv-2023-c4mw6.
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