Proceedings of the National Academy of Sciences - PNAS, 2020-09, Vol.117 (36), p.22090-22100
2020
Details
- Autor(en) / Beteiligte
- Titel
- Intein-mediated cytoplasmic reconstitution of a split toxin enables selective cell ablation in mixed populations and tumor xenografts
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2020-09, Vol.117 (36), p.22090-22100
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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 inteinflanked 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.2006603117Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7486740
- Format
- –
- Schlagworte
- Ablation, Algorithms, Animals, Bacterial Toxins - administration & dosage, Bacterial Toxins - chemistry, Bacterial Toxins - genetics, Bacterial Toxins - metabolism, Biological Sciences, Cell Line, Tumor, Cell surface, Cytoplasm - genetics, Cytoplasm - metabolism, Diphtheria, Diphtheria toxin, Diphtheria Toxin - administration & dosage, Diphtheria Toxin - chemistry, Diphtheria Toxin - genetics, Diphtheria Toxin - metabolism, Drug Delivery Systems - methods, Female, Fragments, Genetic code, Heterografts, Humans, Immunotoxins - administration & dosage, Immunotoxins - chemistry, Immunotoxins - genetics, Immunotoxins - metabolism, Inteins, Mice, Mice, Nude, Neoplasms - drug therapy, Neoplasms - genetics, Neoplasms - metabolism, Populations, Protein Domains, Protein Transport, Proteins, Receptors, Receptors, Cell Surface - genetics, Receptors, Cell Surface - metabolism, Selectivity, Side effects, Subpopulations, Toxicity, Toxins, Tumors, Xenografts, Xenotransplantation