Metal-Dependent Coordination Geometry Controls Autolytic Amide Bond Cleavage to Enable Prodrug Activation.
- 1Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin53706, United States.
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.
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BibTeX
@article{zhong2026metaldependent,
title = {{Metal-Dependent Coordination Geometry Controls Autolytic Amide Bond Cleavage to Enable Prodrug Activation.}},
author = {Zhuoran Zhong and Dariusz Ṡmiłowicz and M Andrey Joaqui-Joaqui and Phuong Nguyen Tran and Leah C Garman and Ilia A Guzei and Eszter Boros},
journal = {Journal of the American Chemical Society},
year = {2026},
month = sep,
doi = {10.1021/jacs.6c15432},
url = {https://europepmc.org/article/MED/42937831},
note = {CC BY},
}
RIS
TY - JOUR
TI - Metal-Dependent Coordination Geometry Controls Autolytic Amide Bond Cleavage to Enable Prodrug Activation.
AU - Zhuoran Zhong
AU - Dariusz Ṡmiłowicz
AU - M Andrey Joaqui-Joaqui
AU - Phuong Nguyen Tran
AU - Leah C Garman
AU - Ilia A Guzei
AU - Eszter Boros
PY - 2026
DA - 2026/09/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c15432
UR - https://europepmc.org/article/MED/42937831
AB - 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.
SN - 0002-7863
SN - 1520-5126
ER -