The chemical synthesis, stability, and activity of MAIT cell prodrug agonists that access MR1 in recycling endosomes
Mucosal-associated invariant T (MAIT) cells are antibacterial effector T cells that react to pyrimidines derived from bacterial riboflavin synthesis presented by the monomorphic molecule MR1. A major challenge in MAIT cell research is that the commonly used MAIT agonist precursor, 5-amino-6-d-ribity...
| Asıl Yazarlar: | , , , , , , , , , , |
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| Materyal Türü: | Journal article |
| Dil: | English |
| Baskı/Yayın Bilgisi: |
American Chemical Society
2020
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| _version_ | 1826283494593003520 |
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| author | Lange, J Anderson, R Marshall, A Chan, S Bilbrough, T Gasser, O Gonzalez-Lopez, C Salio, M Cerundolo, V Hermans, I Painter, G |
| author_facet | Lange, J Anderson, R Marshall, A Chan, S Bilbrough, T Gasser, O Gonzalez-Lopez, C Salio, M Cerundolo, V Hermans, I Painter, G |
| author_sort | Lange, J |
| collection | OXFORD |
| description | Mucosal-associated invariant T (MAIT) cells are antibacterial effector T cells that react to pyrimidines derived from bacterial riboflavin synthesis presented by the monomorphic molecule MR1. A major challenge in MAIT cell research is that the commonly used MAIT agonist precursor, 5-amino-6-d-ribitylaminouracil (5-A-RU), is labile to autoxidation, resulting in a loss of biological activity. Here, we characterize two independent autoxidation processes by LCMS. To overcome the marked instability, we report the synthesis of a 5-A-RU prodrug generated by modification of the 5-amino group with a cleavable valine-citrulline-p-aminobenzyl carbamate. The compound is stable in prodrug form, with the parent amine (i.e., 5-A-RU) released only after enzymatic cleavage. Analysis of the prodrug in vitro and in vivo showed an enhanced MAIT cell activation profile compared to 5-A-RU, which was associated with preferential loading within recycling endosomes, a route used by some natural agonists. This prodrug design therefore overcomes the difficulties associated with 5-A-RU in biological studies and provides an opportunity to explore different presentation pathways. |
| first_indexed | 2024-03-07T00:59:44Z |
| format | Journal article |
| id | oxford-uuid:894d1ec3-1a2f-41b2-bdc4-1f8fe35dfab6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:59:44Z |
| publishDate | 2020 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:894d1ec3-1a2f-41b2-bdc4-1f8fe35dfab62022-03-26T22:23:36ZThe chemical synthesis, stability, and activity of MAIT cell prodrug agonists that access MR1 in recycling endosomesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:894d1ec3-1a2f-41b2-bdc4-1f8fe35dfab6EnglishSymplectic Elements at OxfordAmerican Chemical Society2020Lange, JAnderson, RMarshall, AChan, SBilbrough, TGasser, OGonzalez-Lopez, CSalio, MCerundolo, VHermans, IPainter, GMucosal-associated invariant T (MAIT) cells are antibacterial effector T cells that react to pyrimidines derived from bacterial riboflavin synthesis presented by the monomorphic molecule MR1. A major challenge in MAIT cell research is that the commonly used MAIT agonist precursor, 5-amino-6-d-ribitylaminouracil (5-A-RU), is labile to autoxidation, resulting in a loss of biological activity. Here, we characterize two independent autoxidation processes by LCMS. To overcome the marked instability, we report the synthesis of a 5-A-RU prodrug generated by modification of the 5-amino group with a cleavable valine-citrulline-p-aminobenzyl carbamate. The compound is stable in prodrug form, with the parent amine (i.e., 5-A-RU) released only after enzymatic cleavage. Analysis of the prodrug in vitro and in vivo showed an enhanced MAIT cell activation profile compared to 5-A-RU, which was associated with preferential loading within recycling endosomes, a route used by some natural agonists. This prodrug design therefore overcomes the difficulties associated with 5-A-RU in biological studies and provides an opportunity to explore different presentation pathways. |
| spellingShingle | Lange, J Anderson, R Marshall, A Chan, S Bilbrough, T Gasser, O Gonzalez-Lopez, C Salio, M Cerundolo, V Hermans, I Painter, G The chemical synthesis, stability, and activity of MAIT cell prodrug agonists that access MR1 in recycling endosomes |
| title | The chemical synthesis, stability, and activity of MAIT cell prodrug agonists that access MR1 in recycling endosomes |
| title_full | The chemical synthesis, stability, and activity of MAIT cell prodrug agonists that access MR1 in recycling endosomes |
| title_fullStr | The chemical synthesis, stability, and activity of MAIT cell prodrug agonists that access MR1 in recycling endosomes |
| title_full_unstemmed | The chemical synthesis, stability, and activity of MAIT cell prodrug agonists that access MR1 in recycling endosomes |
| title_short | The chemical synthesis, stability, and activity of MAIT cell prodrug agonists that access MR1 in recycling endosomes |
| title_sort | chemical synthesis stability and activity of mait cell prodrug agonists that access mr1 in recycling endosomes |
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