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

Xuefei Wang; Duan Ni; Yaqin Liu; Shaoyong Lu

doi:10.3389/fchem.2021.682675

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

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

Authors

Xuefei Wang¹, Duan Ni², Yaqin Liu³, Shaoyong Lu^{1

3}

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
² The Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
³ Medicinal Bioinformatics Center, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.

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.

Publication types

Review