{
  "abstract": "We introduce a peptide prodrug activation strategy that employs the trivalent Lewis-acidic metal ions Ga3+, Fe3+, In3+, and Co3+, chelated by triazacyclononanediacetic acid monoamides. The metal chelates trigger rate-tunable, metal-mediated, autolytic amide bond cleavage (TMAC) adjacent to N-methylated and canonical amino acids. Our studies reveal that the four TMAC-compatible metal ions induce amide bond hydrolysis with divergent pH dependence and mechanistic pathways. We subsequently linked Ga3+, Fe3+, In3+, and Co3+ complexes to the N-terminus of a potent cytotoxic cargo, monomethyl auristatin E (MMAE), to produce the proof-of-concept prodrug PD1. In vitro toxicity studies establish IC50 values in HeLa and PC-3 cells that broadly correlate with complex cleavage rates; the metal ion-free PD1 conjugate, the Zn-PD1 complex, as well as the Ga3+, Fe3+, In3+, and Co3+ chelate hydrolysis products alone confer no toxicity. Attachment of a cancer-targeting peptide to the metal chelate, furnishing PD2, enables targeted delivery of the therapeutic payload in vivo, compatible with noninvasive nuclear imaging using positron emission tomography with 68Ga or single-photon computed tomography with 111In. The corresponding natGa-PD2 complex selectively suppressed tumor growth in vivo with minimal off-target toxicity. These studies establish metal identity as a general design parameter for programming amide bond cleavage and introduce TMAC as a versatile platform to engender peptide prodrugs with tunable release kinetics.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin53706, United States."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zhuoran Zhong"
    },
    {
      "affs": [
        0
      ],
      "name": "Dariusz Ṡmiłowicz"
    },
    {
      "affs": [
        0
      ],
      "name": "M Andrey Joaqui-Joaqui"
    },
    {
      "affs": [
        0
      ],
      "name": "Phuong Nguyen Tran",
      "orcid": "0009-0001-6844-6661"
    },
    {
      "affs": [
        0
      ],
      "name": "Leah C Garman",
      "orcid": "0000-0002-3445-652X"
    },
    {
      "affs": [
        0
      ],
      "name": "Ilia A Guzei",
      "orcid": "0000-0003-1976-7386"
    },
    {
      "affs": [
        0
      ],
      "name": "Eszter Boros",
      "orcid": "0000-0002-4186-6586"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4h2mt7z1tysrd.bib",
  "cited_by": 0,
  "doi": "10.1021/jacs.6c15432",
  "fulltext_url": "https://europepmc.org/articles/PMC13632579",
  "id": "4h2mt7z1tysrd",
  "issns": [
    "0002-7863",
    "1520-5126"
  ],
  "landing_url": "https://europepmc.org/article/MED/42937831",
  "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": [
    [
      "openalex",
      "2741|Radiopharmaceutical Chemistry and Applications"
    ]
  ],
  "openalex": "W7212467961",
  "pdf_url": "https://europepmc.org/articles/PMC13632579?pdf=render",
  "pmcid": "PMC13632579",
  "pmid": "42937831",
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4h2mt7z1tysrd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:24Z",
      "native_id": "MED:42937831",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42937831"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2741|Radiopharmaceutical Chemistry and Applications",
      "subfield": "imaging"
    }
  ],
  "title": "Metal-Dependent Coordination Geometry Controls Autolytic Amide Bond Cleavage to Enable Prodrug Activation.",
  "title_text": "Metal-Dependent Coordination Geometry Controls Autolytic Amide Bond Cleavage to Enable Prodrug Activation.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:24Z",
  "url": "https://research.draconitic.com/paper/4h2mt7z1tysrd",
  "venue": "Journal of the American Chemical Society",
  "versions": []
}