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.
Highlights
Protein-protein interactions (PPIs) play a fundamental role in all life events and cellular activities, regulating cells’ lives and death, as well as mediating various biochemical reactions like signal transduction and metabolisms (Li et al, 2020; Luck et al, 2020; Thanasomboon et al, 2020)
The γ-AA3 showed outstanding resistance to enzymatic degradation as demonstrated by HPLC monitoring. These results suggested that γ-AApeptides are a series of promising lead compounds, expanding the peptidomimetics family in the application of blocking p53-MDM2 interaction
In the campaign to tame this class of refractory targets, one of the key powerful armory is peptide-based inhibitors, which mimic the PPI binding partners and readily interfere with the PPI systems of pharmaceutical interests
Summary
Protein-protein interactions (PPIs) play a fundamental role in all life events and cellular activities, regulating cells’ lives and death, as well as mediating various biochemical reactions like signal transduction and metabolisms (Li et al, 2020; Luck et al, 2020; Thanasomboon et al, 2020). PPIs are regarded as the “holy grail” of modern life science and medicine, and they have emerged as a class of promising therapeutic targets toward a plethora of medical conditions (Cunningham et al, 2017; Davenport et al, 2020). Current studies estimated that human interactome consists of about 650,000 PPIs, which represents a fruitful repertoire of drug targets for therapeutics discovery (Vidal et al, 2011). Modulating PPIs is of critical significance in both basic research and clinical translations. It facilitates our better understanding to a wide range of biological events, and constitutes the theoretical basis for current therapeutic agents development. In the era of modern pharmacology, rational design of PPI inhibitor is considered to be a prospective direction for drug discovery, and possess enormous potentials
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