Ribosomal Translation of Fluorinated Non-canonical Amino Acids for Biologically Active Fluorinated Macrocyclic Peptides

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Aug 12

PMID 39129776

Authors

Junjie Wu

Yuchan Wang

Wenfeng Cai

Danyan Chen

Xiangda Peng

Huilei Dong

Jinjing Li

Hongtan Liu

Shuting Shi

Sen Tang

Zhifeng Li

Haiyan Sui

Yan Wang

Chuanliu Wu

Youming Zhang

Xinmiao Fu

Yizhen Yin

Affiliations

Soon will be listed here.

Abstract

Fluorination has emerged as a promising strategy in medicinal chemistry to improve the pharmacological profiles of drug candidates. Similarly, incorporating fluorinated non-canonical amino acids into macrocyclic peptides expands chemical diversity and enhances their pharmacological properties, from improved metabolic stability to enhanced cell permeability and target interactions. However, only a limited number of fluorinated non-canonical amino acids, which are canonical amino acid analogs, have been incorporated into macrocyclic peptides by ribosomes for construction and target-based screening of fluorinated macrocyclic peptides. In this study, we report the ribosomal translation of a series of distinct fluorinated non-canonical amino acids, including mono-to tri-fluorinated variants, as well as fluorinated l-amino acids, d-amino acids, β-amino acids, This enabled the discovery of fluorinated macrocyclic peptides with high affinity for EphA2, and particularly the identification of those exhibiting broad-spectrum activity against Gram-negative bacteria by targeting the BAM complex. This study not only expands the scope of ribosomally translatable fluorinated amino acids but also underscores the versatility of fluorinated macrocyclic peptides as potent therapeutic agents.

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