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Protein-protein Interfaces

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...

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Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions

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Published on: December 1, 2020

Identification of Covalent Cyclic Peptide Inhibitors Targeting Protein-Protein Interactions Using Phage Display.

Sijie Wang¹, Franco F Faucher², Matilde Bertolini³

¹Department of Pathology, School of Medicine, Stanford University, California 94305, United States.

Biorxiv : the Preprint Server for Biology

|November 22, 2024

Summary

This summary is machine-generated.

Researchers developed a new method to discover covalent macrocyclic drugs that target protein-protein interactions. This approach identified irreversible antiviral compounds against SARS-CoV-2, offering potential for long-lasting therapeutic effects.

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Area of Science:

Medicinal Chemistry
Drug Discovery
Biotechnology

Background:

Peptide macrocycles offer metabolic stability and target selectivity for therapeutic applications.
Covalent macrocycles are emerging as potent drug candidates, but their use in disrupting protein-protein interactions is limited.
Developing irreversible covalent inhibitors for protein-protein interactions remains a significant challenge.

Purpose of the Study:

To develop a directed counter-selection method for identifying covalent macrocyclic ligands targeting protein-protein interactions.
To demonstrate the utility of this method using the SARS-CoV-2 Spike-ACE2 interaction.
To identify novel covalent macrocyclic inhibitors with potential antiviral activity.

Main Methods:

Utilized a phage display screening platform with a chemically modified library.
Employed binary and ternary screenings with an aryl fluorosulfate electrophile.
Tested identified inhibitors against the SARS-CoV-2 Spike-ACE2 protein-protein interaction.

Main Results:

Successfully identified multiple covalent macrocyclic inhibitors of the SARS-CoV-2 Spike-ACE2 interaction.
Demonstrated irreversible antiviral activity against live SARS-CoV-2 virus.
Confirmed the covalent binding mechanism responsible for the sustained antiviral effect.

Conclusions:

The developed screening platform is effective for discovering covalent macrocyclic drugs targeting protein-protein interactions.
This approach can yield irreversible inhibitors with potential for long-lasting therapeutic benefits.
The identified compounds show promise for developing new treatments against viral infections like COVID-19.