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Design and Application of a DNA-Encoded Macrocyclic Peptide Library.

Zhengrong Zhu¹, Alex Shaginian¹, LaShadric C Grady¹

¹GlaxoSmithKline , 200 Cambridge Park Dr., Cambridge, Massachusetts 02140, United States.

ACS Chemical Biology

|November 30, 2017

Summary

This summary is machine-generated.

Researchers developed a large library of DNA-encoded macrocyclic peptides for drug discovery. Selected peptides showed activity against therapeutic targets like VHL and RSV N protein, confirming their potential.

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Area of Science:

Medicinal Chemistry
Molecular Biology
Drug Discovery

Background:

Macrocyclic peptides offer unique therapeutic properties.
DNA-encoded libraries (DELs) enable the screening of vast chemical spaces.
Targeting proteins like VHL and RSV N protein is crucial for disease treatment.

Purpose of the Study:

To design and synthesize a large DNA-encoded macrocyclic peptide library.
To identify novel peptide binders against VHL and RSV N protein.
To validate the activity of selected peptides.

Main Methods:

Synthesis of a DNA-encoded library with 2.4 × 10^12 macrocyclic peptide members.
Incorporation of 4-20 natural and non-natural amino acids.
Affinity-based selection against VHL and RSV N protein targets.
Resynthesis and activity validation of selected DNA-free peptides.

Main Results:

Successful design and synthesis of a diverse DNA-encoded macrocyclic peptide library.
Identification of peptide binders through affinity selection against VHL and RSV N protein.
Confirmation of biological activity for selected peptides after resynthesis.

Conclusions:

DNA-encoded macrocyclic peptide libraries are effective for discovering novel therapeutic agents.
The identified peptides demonstrate potential for further development against VHL and RSV N protein.
This approach accelerates the hit identification process in drug discovery.