{
  "abstract": "Lysosome-targeting chimeras (LYTACs) induce the internalization of extracellular and membrane-associated proteins by routing them to lysosomes via endogenous receptors, such as the insulin-like growth factor-2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor. While current IGF2R ligands are effective, expanding the LYTAC toolkit with structurally simple and synthetically accessible ligands remains a practical necessity. Here, we first validated that previously reported dimeric and monomeric peptides induce robust internalization, establishing them as effective IGF2R-targeting LYTAC ligands. To further optimize the peptide architecture, we performed systematic mutational scanning on its monomeric sequence to simplify the peptide architecture. We identified the L4 variant, which features a single leucine substitution at the fourth position. This optimized monomer induces greater internalization efficiency than the previously reported wild-type monomeric peptide ligand. To demonstrate its utility, we conjugated the L4 recruiter to a specific PCSK9 binder. The resulting bifunctional molecule successfully induced the dose- and time-dependent internalization of PCSK9. Collectively, these findings establish several peptide variants as practical and highly effective building blocks for the development of extracellular protein internalization platforms.",
  "abstract_shown": true,
  "affiliations": [
    "School of Pharmacy, Lachman Institute of Pharmaceutical Development, University of Wisconsin-Madison, Madison, Wisconsin, USA.",
    "Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.",
    "Chemical Biology, Novo Nordisk US R&D, Lexington, Massachusetts, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yuan Zhao"
    },
    {
      "affs": [
        1
      ],
      "name": "Yaxian Liao"
    },
    {
      "affs": [
        0
      ],
      "name": "Xuankun Chen",
      "orcid": "0000-0001-6006-7360"
    },
    {
      "affs": [
        0
      ],
      "name": "Deqin Cai",
      "orcid": "0000-0002-3143-2362"
    },
    {
      "affs": [
        0
      ],
      "name": "Regina Stasser de Gonzalez"
    },
    {
      "affs": [
        0
      ],
      "name": "Hua Tang",
      "orcid": "0000-0002-3342-8789"
    },
    {
      "affs": [
        2
      ],
      "name": "Florence M Brunel"
    },
    {
      "affs": [
        2
      ],
      "name": "Nick Cox",
      "orcid": "0009-0008-2413-5627"
    },
    {
      "affs": [
        2
      ],
      "name": "Joseph Stock"
    },
    {
      "affs": [
        2
      ],
      "name": "Guangsen Fu"
    },
    {
      "affs": [
        2
      ],
      "name": "Alexander N Zaykov",
      "orcid": "0000-0001-6908-9195"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Weiping Tang",
      "orcid": "0000-0002-0039-3196"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6j5z5j942fzpw.bib",
  "cited_by": 0,
  "doi": "10.1002/cbic.70587",
  "fulltext_url": "https://europepmc.org/articles/PMC13717051",
  "id": "6j5z5j942fzpw",
  "issns": [
    "1439-4227",
    "1439-7633"
  ],
  "landing_url": "https://europepmc.org/article/MED/42952087",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "1312|RNA Interference and Gene Delivery"
    ]
  ],
  "openalex": "W7224281275",
  "pdf_url": "https://europepmc.org/articles/PMC13717051?pdf=render",
  "pmcid": "PMC13717051",
  "pmid": "42952087",
  "published": "2026-10-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/6j5z5j942fzpw.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:33Z",
      "native_id": "MED:42952087",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42952087"
    },
    {
      "first_seen": "2026-11-02T12:21:26Z",
      "native_id": "PMC13717051",
      "source": "pmc",
      "url": "https://doi.org/10.1002/cbic.70587"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA Interference and Gene Delivery",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Development of Highly Efficient Lysosome-Targeting Peptide Ligands for the Internalization of Extracellular Proteins.",
  "title_text": "Development of Highly Efficient Lysosome-Targeting Peptide Ligands for the Internalization of Extracellular Proteins.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:21:26Z",
  "url": "https://research.draconitic.com/paper/6j5z5j942fzpw",
  "venue": "Chembiochem : a European journal of chemical biology",
  "versions": []
}