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Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry
[Image: see text] Dynamic covalent exchange cascades with cellular thiols are of interest to deliver substrates to the cytosol and to inhibit the entry of viruses. The best transporters and inhibitors known today are cyclic cascade exchangers (CAXs), producing a new exchanger with every exchange, mo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9063988/ https://www.ncbi.nlm.nih.gov/pubmed/35615714 http://dx.doi.org/10.1021/jacsau.2c00017 |
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author | Lim, Bumhee Kato, Takehiro Besnard, Celine Poblador Bahamonde, Amalia I. Sakai, Naomi Matile, Stefan |
author_facet | Lim, Bumhee Kato, Takehiro Besnard, Celine Poblador Bahamonde, Amalia I. Sakai, Naomi Matile, Stefan |
author_sort | Lim, Bumhee |
collection | PubMed |
description | [Image: see text] Dynamic covalent exchange cascades with cellular thiols are of interest to deliver substrates to the cytosol and to inhibit the entry of viruses. The best transporters and inhibitors known today are cyclic cascade exchangers (CAXs), producing a new exchanger with every exchange, mostly cyclic oligochalcogenides, particularly disulfides. The objective of this study was to expand the dynamic covalent chalcogen exchange cascades in thiol-mediated uptake by inserting pnictogen relays. A family of pnictogen-expanded cyclic disulfides covering As(III), Sb(III), and Bi(III) is introduced. Their ability to inhibit thiol-mediated cytosolic delivery is explored with fluorescently labeled CAXs as transporters. The promise of inhibiting viral entry is assessed with SARS-CoV-2 lentiviral vectors. Oxygen-bridged seven-membered 1,3,2-dithiabismepane rings are identified as privileged scaffolds. The same holds for six-membered 1,3,2-dithiarsinane rings made from asparagusic acid and para-aminophenylarsine oxide, which are inactive or toxic when used alone. These chemically complementary Bi(III) and As(III) cascade exchangers inhibit both thiol-mediated cytosolic delivery and SARS-CoV-2 lentivector uptake at concentrations of 10 μM or lower. Crystal structures, computational models, and exchange kinetics support that lentivector entry inhibition of the contracted dithiarsinane and the expanded dithiabismepane rings coincides with exchange cascades that occur without the release of the pnictogen relay and benefit from noncovalent pnictogen bonds. The identified leads open perspectives regarding drug delivery as well as unorthodox approaches toward dynamic covalent inhibition of cellular entry. |
format | Online Article Text |
id | pubmed-9063988 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-90639882022-05-03 Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry Lim, Bumhee Kato, Takehiro Besnard, Celine Poblador Bahamonde, Amalia I. Sakai, Naomi Matile, Stefan JACS Au [Image: see text] Dynamic covalent exchange cascades with cellular thiols are of interest to deliver substrates to the cytosol and to inhibit the entry of viruses. The best transporters and inhibitors known today are cyclic cascade exchangers (CAXs), producing a new exchanger with every exchange, mostly cyclic oligochalcogenides, particularly disulfides. The objective of this study was to expand the dynamic covalent chalcogen exchange cascades in thiol-mediated uptake by inserting pnictogen relays. A family of pnictogen-expanded cyclic disulfides covering As(III), Sb(III), and Bi(III) is introduced. Their ability to inhibit thiol-mediated cytosolic delivery is explored with fluorescently labeled CAXs as transporters. The promise of inhibiting viral entry is assessed with SARS-CoV-2 lentiviral vectors. Oxygen-bridged seven-membered 1,3,2-dithiabismepane rings are identified as privileged scaffolds. The same holds for six-membered 1,3,2-dithiarsinane rings made from asparagusic acid and para-aminophenylarsine oxide, which are inactive or toxic when used alone. These chemically complementary Bi(III) and As(III) cascade exchangers inhibit both thiol-mediated cytosolic delivery and SARS-CoV-2 lentivector uptake at concentrations of 10 μM or lower. Crystal structures, computational models, and exchange kinetics support that lentivector entry inhibition of the contracted dithiarsinane and the expanded dithiabismepane rings coincides with exchange cascades that occur without the release of the pnictogen relay and benefit from noncovalent pnictogen bonds. The identified leads open perspectives regarding drug delivery as well as unorthodox approaches toward dynamic covalent inhibition of cellular entry. American Chemical Society 2022-03-24 /pmc/articles/PMC9063988/ /pubmed/35615714 http://dx.doi.org/10.1021/jacsau.2c00017 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Lim, Bumhee Kato, Takehiro Besnard, Celine Poblador Bahamonde, Amalia I. Sakai, Naomi Matile, Stefan Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry |
title | Pnictogen-Centered Cascade Exchangers for Thiol-Mediated
Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic
Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry |
title_full | Pnictogen-Centered Cascade Exchangers for Thiol-Mediated
Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic
Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry |
title_fullStr | Pnictogen-Centered Cascade Exchangers for Thiol-Mediated
Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic
Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry |
title_full_unstemmed | Pnictogen-Centered Cascade Exchangers for Thiol-Mediated
Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic
Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry |
title_short | Pnictogen-Centered Cascade Exchangers for Thiol-Mediated
Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic
Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry |
title_sort | pnictogen-centered cascade exchangers for thiol-mediated
uptake: as(iii)-, sb(iii)-, and bi(iii)-expanded cyclic
disulfides as inhibitors of cytosolic delivery and viral entry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9063988/ https://www.ncbi.nlm.nih.gov/pubmed/35615714 http://dx.doi.org/10.1021/jacsau.2c00017 |
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