Tricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cells
The intracellular environment hosts a large number of cancer- and other disease-relevant human proteins. Targeting these with internalized antibodies would allow therapeutic modulation of hitherto undruggable pathways, such as those mediated by protein–protein interactions. However, one of the major...
| Hlavní autoři: | , , , , |
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| Médium: | Journal article |
| Jazyk: | English |
| Vydáno: |
Springer Nature
2022
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| _version_ | 1826308312071667712 |
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| author | Tietz, O Cortezon Tamarit, F Chalk, R Able, S Vallis, K |
| author_facet | Tietz, O Cortezon Tamarit, F Chalk, R Able, S Vallis, K |
| author_sort | Tietz, O |
| collection | OXFORD |
| description | The intracellular environment hosts a large number of cancer- and other disease-relevant human proteins. Targeting these with internalized antibodies would allow therapeutic modulation of hitherto undruggable pathways, such as those mediated by protein–protein interactions. However, one of the major obstacles in intracellular targeting is the entrapment of biomacromolecules in the endosome. Here we report an approach to delivering antibodies and antibody fragments into the cytosol and nucleus of cells using trimeric cell-penetrating peptides (CPPs). Four trimers, based on linear and cyclic sequences of the archetypal CPP Tat, are significantly more potent than monomers and can be tuned to function by direct interaction with the plasma membrane or escape from vesicle-like bodies. These studies identify a tricyclic Tat construct that enables intracellular delivery of functional immunoglobulin-G antibodies and Fab fragments that bind intracellular targets in the cytosol and nuclei of live cells at effective concentrations as low as 1 μM. |
| first_indexed | 2024-03-07T07:16:06Z |
| format | Journal article |
| id | oxford-uuid:f3c9a70f-2fd9-4b50-bd9f-c7b84afefd81 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:16:06Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:f3c9a70f-2fd9-4b50-bd9f-c7b84afefd812022-08-10T09:35:25ZTricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f3c9a70f-2fd9-4b50-bd9f-c7b84afefd81EnglishSymplectic ElementsSpringer Nature2022Tietz, OCortezon Tamarit, FChalk, RAble, SVallis, KThe intracellular environment hosts a large number of cancer- and other disease-relevant human proteins. Targeting these with internalized antibodies would allow therapeutic modulation of hitherto undruggable pathways, such as those mediated by protein–protein interactions. However, one of the major obstacles in intracellular targeting is the entrapment of biomacromolecules in the endosome. Here we report an approach to delivering antibodies and antibody fragments into the cytosol and nucleus of cells using trimeric cell-penetrating peptides (CPPs). Four trimers, based on linear and cyclic sequences of the archetypal CPP Tat, are significantly more potent than monomers and can be tuned to function by direct interaction with the plasma membrane or escape from vesicle-like bodies. These studies identify a tricyclic Tat construct that enables intracellular delivery of functional immunoglobulin-G antibodies and Fab fragments that bind intracellular targets in the cytosol and nuclei of live cells at effective concentrations as low as 1 μM. |
| spellingShingle | Tietz, O Cortezon Tamarit, F Chalk, R Able, S Vallis, K Tricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cells |
| title | Tricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cells |
| title_full | Tricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cells |
| title_fullStr | Tricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cells |
| title_full_unstemmed | Tricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cells |
| title_short | Tricyclic cell-penetrating peptides for efficient delivery of functional antibodies into cancer cells |
| title_sort | tricyclic cell penetrating peptides for efficient delivery of functional antibodies into cancer cells |
| work_keys_str_mv | AT tietzo tricycliccellpenetratingpeptidesforefficientdeliveryoffunctionalantibodiesintocancercells AT cortezontamaritf tricycliccellpenetratingpeptidesforefficientdeliveryoffunctionalantibodiesintocancercells AT chalkr tricycliccellpenetratingpeptidesforefficientdeliveryoffunctionalantibodiesintocancercells AT ables tricycliccellpenetratingpeptidesforefficientdeliveryoffunctionalantibodiesintocancercells AT vallisk tricycliccellpenetratingpeptidesforefficientdeliveryoffunctionalantibodiesintocancercells |