ArticleProceedings of the National Academy of Sciences of the United States of America2020
Intein-mediated cytoplasmic reconstitution of a split toxin enables selective cell ablation in mixed populations and tumor xenografts.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed, 17 citations in OpenAlex.
- A Chemical Framework for Engineering Extracellular Vesicles' Biointerface to Advance Precision Therapeutics.Advanced materials (Deerfield Beach, Fla.) · 2026Review
- Development of a split-toxin CRISPR screening platform to systematically identify regulators of human myoblast fusion.Nature communications · 2026Article
- SiMPl-GS: Advancing Cell Line Development via Synthetic Selection Marker for Next-Generation Biopharmaceutical Production.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Int&in: A machine learning-based web server for active split site identification in inteins.Protein science : a publication of the Protein Society · 2024Article
- Development of Synthetic mRNAs Encoding Split Cytotoxic Proteins for Selective Cell Elimination Based on Specific Protein Detection.Pharmaceutics · 2023Article
- Expanding the Therapeutic Window of EGFR-Targeted PE24 Immunotoxin for EGFR-Overexpressing Cancers by Tailoring the EGFR Binding Affinity.International journal of molecular sciences · 2022Article
- Strategies to mitigate the on- and off-target toxicities of recombinant immunotoxins: an antibody engineering perspective.Antibody therapeutics · 2022Review
- Inteins as Drug Targets and Therapeutic Tools.Frontiers in molecular biosciences · 2022Review
- Reactive Chlorine Species Reversibly Inhibit DnaB Protein Splicing in Mycobacteria.Microbiology spectrum · 2021Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The application of proteinaceous toxins for cell ablation is limited by their high on- and off-target toxicity, severe side effects, and a narrow therapeutic window. The selectivity of targeting can be improved by intein-based toxin reconstitution from two dysfunctional fragments provided their cytoplasmic delivery via independent, selective pathways. While the reconstitution of proteins from genetically encoded elements has been explored, exploiting cell-surface receptors for boosting selectivity has not been attained. We designed a robust splitting algorithm and achieved reliable cytoplasmic reconstitution of functional diphtheria toxin from engineered intein-flanked fragments upon receptor-mediated delivery of one of them to the cells expressing the counterpart. Retargeting the delivery machinery toward different receptors overexpressed in cancer cells enables selective ablation of specific subpopulations in mixed cell cultures. In a mouse model, the transmembrane delivery of a split-toxin construct potently inhibits the growth of xenograft tumors expressing the split counterpart. Receptor-mediated delivery of engineered split proteins provides a platform for precise therapeutic and experimental ablation of tumors or desired cell populations while also greatly expanding the applicability of the intein-based protein transsplicing.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.