Work

Advancements in Loop Cyclization Approaches for Enhanced Peptide Therapeutics for Targeting Protein–Protein Interactions

Year: 2024

Type: article

Abstract: Protein-protein interactions (PPIs) are pivotal in regulating cellular functions and life processes, making them promising therapeutic targets in modern medicine. Despite their potential, developing PPI inhibitors poses significant challenges due to their large and shallow interfaces that complicate ligand binding. This study focuses on mimicking peptide loops as a strategy for PPI inhibition, utilizing synthetic peptide loops for replicating critical binding regions. This work explores turn-inducing elements and highlights the importance of proline in promoting favorable conformations for lactamization, yielding high-purity cyclic peptides. Notably, our one-pot method offers enhanced versatility and represents a robust strategy for efficient and selective macrolactamization, expanding the scope of peptide synthesis methodologies. This approach, validated through the synthesis of AAV capsid-derived loops, offers a robust platform for developing peptide-based therapeutics and highlights the potential of peptide macrocycles in overcoming PPI drug discovery challenges and advancing the development of new therapeutics.

Source: The Journal of Organic Chemistry

DOI: 10.1021/acs.joc.4c02178

Authors: Lucia Lombardi, Luke A. Granger, Robin J. Shattock, Daryl R. Williams

Institution: Imperial College London

Language: English

Topic: Chemical Synthesis and Analysis

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $4,500

Funders: Eli Lilly and Company, Wellcome Trust, Engineering and Physical Sciences Research Council