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Review
. 2021 May 4:9:682675.
doi: 10.3389/fchem.2021.682675. eCollection 2021.

Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

Xuefei Wang  1 , Duan Ni  2 , Yaqin Liu  3 , Shaoyong Lu  1   3
Affiliations
Review

Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

Xuefei Wang et al. Front Chem. .

Abstract

Protein-protein interactions (PPIs) are well-established as a class of promising drug targets for their implications in a wide range of biological processes. However, drug development toward PPIs is inevitably hampered by their flat and wide interfaces, which generally lack suitable pockets for ligand binding, rendering most PPI systems "undruggable." Here, we summarized drug design strategies for developing peptide-based PPI inhibitors. Importantly, several quintessential examples toward well-established PPI targets such as Bcl-2 family members, p53-MDM2, as well as APC-Asef are presented to illustrate the detailed schemes for peptide-based PPI inhibitor development and optimizations. This review supplies a comprehensive overview of recent progresses in drug discovery targeting PPIs through peptides or peptidomimetics, and will shed light on future therapeutic agent development toward the historically "intractable" PPI systems.

Keywords: drug discovery; peptide; peptidomimetics; protein-protein interaction; undruggable.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Current representative mainstream strategies for peptidomimetic PPI inhibitors design and optimization.
Figure 2
Figure 2
The chemical structure of α-peptide, chiral PNA, γ-AApeptide, Sulfono-γ-AApeptide, and 1:1 α/Sulfono- γ-AApeptide.
Figure 3
Figure 3
Peptide-based PPI inhibitors targeting Bcl-2 Family PPIs. (A) Structural overview of the Bcl-xl/Bak peptide PPI complex (PDB ID: 1bxl). Bcl-xl and Bak are shown in gray and green, respectively. Hydrophobic residues along the PPI interface are highlighted in purple (Bcl-xl) and green (Bak peptide) stick correspondingly. (B) Development scheme of Terephthalamide derivatives as BH3 mimetics peptide PPI inhibitors. (C) Binding interactions between Biphenyl-cross-linked Noxa peptide (blue carbon atoms) and Mcl-1 (gray carbon atoms). The key residues of side chains in Mcl-1 are labeled in yellow. The red dashed lines represent the hydrogen bonds between Biphenyl-cross-linked Noxa peptide and Mcl-1. (D) Development scheme of Noxa stapled peptides as Mcl-1 inhibitors.
Figure 4
Figure 4
Peptide-based PPI inhibitors targeting p53-MDM2. (A) The structure of γ-AApeptide γ-AA3. (B) The structure of Sulfono-γ-AApeptide PS1, PS10 and PS11. (C) The structre of D-Sulfono-γ-AApeptide γ-AA4. (D) The scheme of chemical modifications for α/Sulfono- γ-AApeptides.
Figure 5
Figure 5
Peptide-based PPI inhibitors targeting APC-Asef PPI. (A) Structural overview of MAI150/APC PPI complex (PDB ID: 5IZ6). APC is shown as a solvent-accessible surface (pink), and MAI-150 is depicted by sticks (carbon atoms: cyan). (B) Development scheme of MAI analogs as APC-Asef PPI inhibitors. (C) Binding interactions between MAI-400 (carbon atoms: yellow) and APC (carbon atoms: pink). The red dashed lines represent the intramolecular hydrogen bonds between MAI-400 and APC.
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References

    1. Adams J. M., Cory S. (2018). The Bcl-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 25, 27–36. 10.1038/cdd.2017.161 - DOI - PMC - PubMed
    1. Akram O. N., DeGraff D. J., Sheehan J. H., Tilley W. D., Matusik R. J., Ahn J. M., et al. . (2014). Tailoring peptidomimetics for targeting protein-protein interactions. Mol. Cancer Res. 12, 967–978. 10.1158/1541-7786.MCR-13-0611 - DOI - PubMed
    1. Ashkenazi A., Fairbrother W. J., Leverson J. D., Souers A. J. (2017). From basic apoptosis discoveries to advanced selective Bcl-2 family inhibitors. Nat. Rev. Drug Discov. 16, 273–284. 10.1038/nrd.2016.253 - DOI - PubMed
    1. Bartling C. R. O., Jensen T. M. T., Henry S. M., Colliander A. L., Sereikaite V., Wenzler M., et al. . (2021). Targeting the App-Mint2 protein-protein interaction with a peptide-based inhibitor reduces amyloid-beta formation. J. Am. Chem. Soc. 143, 891–901. 10.1021/jacs.0c10696 - DOI - PMC - PubMed
    1. Beekman A. M., O'Connell M. A., Howell L. A. (2017). Peptide-directed binding for the discovery of modulators of alpha-helix-mediated protein-protein interactions: proof-of-concept studies with the apoptosis regulator Mcl-1. Angew. Chem. Int. Ed. Engl. 56, 10446–10450. 10.1002/anie.201705008 - DOI - PMC - PubMed