γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells
Connecting two small molecules, such as ligands, fluorophores, or lipids, together via a linker with amide bonds is a widely used strategy to generate synthetic bifunctional molecules for various biological and biomedical applications. Such bifunctional molecules have been used in live-cell experime...
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| مؤلفون آخرون: | , , , , , , , , , |
| منشور في: |
2024
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| _version_ | 1852025035091345408 |
|---|---|
| author | Kai Tahara (9245264) |
| author2 | Akinobu Nakamura (414876) Xiaotong Wang (276499) Keishi Mitamura (20299691) Yuki Ichihashi (3775042) Keiko Kano (493477) Emi Mishiro-Sato (14426149) Kazuhiro Aoki (56255) Yasuteru Urano (656510) Toru Komatsu (1521958) Shinya Tsukiji (1919149) |
| author2_role | author author author author author author author author author author |
| author_facet | Kai Tahara (9245264) Akinobu Nakamura (414876) Xiaotong Wang (276499) Keishi Mitamura (20299691) Yuki Ichihashi (3775042) Keiko Kano (493477) Emi Mishiro-Sato (14426149) Kazuhiro Aoki (56255) Yasuteru Urano (656510) Toru Komatsu (1521958) Shinya Tsukiji (1919149) |
| author_role | author |
| dc.creator.none.fl_str_mv | Kai Tahara (9245264) Akinobu Nakamura (414876) Xiaotong Wang (276499) Keishi Mitamura (20299691) Yuki Ichihashi (3775042) Keiko Kano (493477) Emi Mishiro-Sato (14426149) Kazuhiro Aoki (56255) Yasuteru Urano (656510) Toru Komatsu (1521958) Shinya Tsukiji (1919149) |
| dc.date.none.fl_str_mv | 2024-11-21T04:31:48Z |
| dc.identifier.none.fl_str_mv | 10.1021/acschembio.4c00432.s002 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/_Secretase_Cleaves_Bifunctional_Fatty_Acid-Conjugated_Small_Molecules_with_Amide_Bonds_in_Mammalian_Cells/27872738 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biophysics Biochemistry Cell Biology Genetics Molecular Biology Neuroscience Pharmacology Biotechnology Immunology Cancer Hematology Chemical Sciences not elsewhere classified several different types previously overlooked consideration molecule ligand trimethoprim chemical biology research targeting bifunctional molecule linked bifunctional compounds based bifunctional molecules two small molecules conjugated small molecules widely used strategy undergo intracellular degradation lack lipid modification first identified γ bifunctional molecules intracellular degradation various biological together via next investigated n </ hydrophobic groups findings highlight cell experiments bond cleavage biomedical applications |
| dc.title.none.fl_str_mv | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | Connecting two small molecules, such as ligands, fluorophores, or lipids, together via a linker with amide bonds is a widely used strategy to generate synthetic bifunctional molecules for various biological and biomedical applications. Such bifunctional molecules have been used in live-cell experiments under the assumption that they should be stable in cells. However, we recently found that a membrane-targeting bifunctional molecule, composed of a lipopeptide and the small-molecule ligand trimethoprim, referred to as mgcTMP, underwent amide-bond cleavage in mammalian cells. In this work, we first identified γ-secretase as the major protease degrading mgcTMP in cells. We next investigated the intracellular degradation of several different types of amide-linked bifunctional compounds and found that <i>N</i>-terminally fatty acid-conjugated small molecules are susceptible to γ-secretase-mediated amide-bond cleavage. In contrast, amide-linked bifunctional molecules composed of two small molecules, such as ligands and hydrophobic groups, which lack lipid modification, did not undergo intracellular degradation. These findings highlight a previously overlooked consideration for the development and application of lipid-based bifunctional molecules in chemical biology research. |
| eu_rights_str_mv | openAccess |
| id | Manara_c63bdeab474cd7613faa6ccb10bfecd2 |
| identifier_str_mv | 10.1021/acschembio.4c00432.s002 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/27872738 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian CellsKai Tahara (9245264)Akinobu Nakamura (414876)Xiaotong Wang (276499)Keishi Mitamura (20299691)Yuki Ichihashi (3775042)Keiko Kano (493477)Emi Mishiro-Sato (14426149)Kazuhiro Aoki (56255)Yasuteru Urano (656510)Toru Komatsu (1521958)Shinya Tsukiji (1919149)BiophysicsBiochemistryCell BiologyGeneticsMolecular BiologyNeurosciencePharmacologyBiotechnologyImmunologyCancerHematologyChemical Sciences not elsewhere classifiedseveral different typespreviously overlooked considerationmolecule ligand trimethoprimchemical biology researchtargeting bifunctional moleculelinked bifunctional compoundsbased bifunctional moleculestwo small moleculesconjugated small moleculeswidely used strategyundergo intracellular degradationlack lipid modificationfirst identified γbifunctional moleculesintracellular degradationvarious biologicaltogether vianext investigatedn </hydrophobic groupsfindings highlightcell experimentsbond cleavagebiomedical applicationsConnecting two small molecules, such as ligands, fluorophores, or lipids, together via a linker with amide bonds is a widely used strategy to generate synthetic bifunctional molecules for various biological and biomedical applications. Such bifunctional molecules have been used in live-cell experiments under the assumption that they should be stable in cells. However, we recently found that a membrane-targeting bifunctional molecule, composed of a lipopeptide and the small-molecule ligand trimethoprim, referred to as mgcTMP, underwent amide-bond cleavage in mammalian cells. In this work, we first identified γ-secretase as the major protease degrading mgcTMP in cells. We next investigated the intracellular degradation of several different types of amide-linked bifunctional compounds and found that <i>N</i>-terminally fatty acid-conjugated small molecules are susceptible to γ-secretase-mediated amide-bond cleavage. In contrast, amide-linked bifunctional molecules composed of two small molecules, such as ligands and hydrophobic groups, which lack lipid modification, did not undergo intracellular degradation. These findings highlight a previously overlooked consideration for the development and application of lipid-based bifunctional molecules in chemical biology research.2024-11-21T04:31:48ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acschembio.4c00432.s002https://figshare.com/articles/dataset/_Secretase_Cleaves_Bifunctional_Fatty_Acid-Conjugated_Small_Molecules_with_Amide_Bonds_in_Mammalian_Cells/27872738CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/278727382024-11-21T04:31:48Z |
| spellingShingle | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells Kai Tahara (9245264) Biophysics Biochemistry Cell Biology Genetics Molecular Biology Neuroscience Pharmacology Biotechnology Immunology Cancer Hematology Chemical Sciences not elsewhere classified several different types previously overlooked consideration molecule ligand trimethoprim chemical biology research targeting bifunctional molecule linked bifunctional compounds based bifunctional molecules two small molecules conjugated small molecules widely used strategy undergo intracellular degradation lack lipid modification first identified γ bifunctional molecules intracellular degradation various biological together via next investigated n </ hydrophobic groups findings highlight cell experiments bond cleavage biomedical applications |
| status_str | publishedVersion |
| title | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells |
| title_full | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells |
| title_fullStr | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells |
| title_full_unstemmed | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells |
| title_short | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells |
| title_sort | γ‑Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells |
| topic | Biophysics Biochemistry Cell Biology Genetics Molecular Biology Neuroscience Pharmacology Biotechnology Immunology Cancer Hematology Chemical Sciences not elsewhere classified several different types previously overlooked consideration molecule ligand trimethoprim chemical biology research targeting bifunctional molecule linked bifunctional compounds based bifunctional molecules two small molecules conjugated small molecules widely used strategy undergo intracellular degradation lack lipid modification first identified γ bifunctional molecules intracellular degradation various biological together via next investigated n </ hydrophobic groups findings highlight cell experiments bond cleavage biomedical applications |