{
  "id": 6260409,
  "title": "Expanding Macrocyclic Topology through Cysteine-to-N-Terminal Cyclisation Enables Covalent Peptide Inhibitor Discovery",
  "url": "https://urgent.news/2026/09/08/expanding-macrocyclic-topology-through-cysteine-to-n-terminal",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-08T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749435v1?rss=1"
  },
  "original_language": "en",
  "account": "Macrocyclic peptides possess the ability to interact with difficult protein targets while maintaining desirable drug-like characteristics. These peptides exhibit strong binding affinity, making them suitable for proximity-driven covalent inhibition via latent electrophiles. Phage display allows for the screening of vast macrocyclic peptide libraries; yet, current libraries predominantly utilize cysteine-mediated cyclisation, constraining the variety of macrocyclic conformations available for ligand exploration. Researchers have now devised a gentle and efficient cyclisation method utilizing bromomethyl picolinaldehyde (BMP) linker that reacts with both a cysteine side chain and the peptide N-terminus, creating a previously unexplored macrocyclic structure with pyridine and imidazolidinone rings. This chemistry is compatible with phage display, enabling the screening of BMP-cyclised peptide libraries against plasma kallikrein, resulting in a highly effective macrocyclic inhibitor. The BMP-cyclised peptide exhibited considerably higher potency compared to peptides cyclised through disulfide bonds or the commonly used linker 1,4-bis(bromomethyl)benzene (DBMB). Additionally, when compared to a DBMB-cyclised library, BMP-mediated cyclisation revealed binding motifs that were not identified through traditional cysteine-to-cysteine cyclisation. Lastly, the application of positional sulfur(VI) fluoride exchange (SuFEx) electrophile scanning transformed the BMP-derived hit into a selective covalent macrocyclic activity-based probe, capable of labeling plasma kallikrein in human plasma. Overall, these discoveries demonstrate BMP-mediated cyclisation as a flexible approach for broadening the topological variety of phage-displayed macrocycles and expediting the identification of both reversible and covalent macrocyclic peptide ligands.",
  "summary": "Macrocyclic peptides are an attractive therapeutic modality capable of engaging challenging protein targets while retaining many favourable drug-like properties. Their high-affinity binding also provides an ideal framework for proximity-driven covalent inhibition through incorporation of latent electrophiles. Phage display enables the high-throughput screening of billion-member macrocyclic…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}