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Automated Flow Synthesis of Peptide–PNA Conjugates
[Image: see text] Antisense peptide nucleic acids (PNAs) have yet to translate to the clinic because of poor cellular uptake, limited solubility, and rapid elimination. Cell-penetrating peptides (CPPs) covalently attached to PNAs may facilitate clinical development by improving uptake into cells. We...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8874765/ https://www.ncbi.nlm.nih.gov/pubmed/35233452 http://dx.doi.org/10.1021/acscentsci.1c01019 |
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author | Li, Chengxi Callahan, Alex J. Phadke, Kruttika S. Bellaire, Bryan Farquhar, Charlotte E. Zhang, Genwei Schissel, Carly K. Mijalis, Alexander J. Hartrampf, Nina Loas, Andrei Verhoeven, David E. Pentelute, Bradley L. |
author_facet | Li, Chengxi Callahan, Alex J. Phadke, Kruttika S. Bellaire, Bryan Farquhar, Charlotte E. Zhang, Genwei Schissel, Carly K. Mijalis, Alexander J. Hartrampf, Nina Loas, Andrei Verhoeven, David E. Pentelute, Bradley L. |
author_sort | Li, Chengxi |
collection | PubMed |
description | [Image: see text] Antisense peptide nucleic acids (PNAs) have yet to translate to the clinic because of poor cellular uptake, limited solubility, and rapid elimination. Cell-penetrating peptides (CPPs) covalently attached to PNAs may facilitate clinical development by improving uptake into cells. We report an efficient technology that utilizes a fully automated fast-flow instrument to manufacture CPP-conjugated PNAs (PPNAs) in a single shot. The machine is rapid, with each amide bond being formed in 10 s. Anti-IVS2-654 PPNA synthesized with this instrument presented threefold activity compared to transfected PNA in a splice-correction assay. We demonstrated the utility of this approach by chemically synthesizing eight anti-SARS-CoV-2 PPNAs in 1 day. A PPNA targeting the 5′ untranslated region of SARS-CoV-2 genomic RNA reduced the viral titer by over 95% in a live virus infection assay (IC(50) = 0.8 μM). Our technology can deliver PPNA candidates to further investigate their potential as antiviral agents. |
format | Online Article Text |
id | pubmed-8874765 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-88747652022-02-28 Automated Flow Synthesis of Peptide–PNA Conjugates Li, Chengxi Callahan, Alex J. Phadke, Kruttika S. Bellaire, Bryan Farquhar, Charlotte E. Zhang, Genwei Schissel, Carly K. Mijalis, Alexander J. Hartrampf, Nina Loas, Andrei Verhoeven, David E. Pentelute, Bradley L. ACS Cent Sci [Image: see text] Antisense peptide nucleic acids (PNAs) have yet to translate to the clinic because of poor cellular uptake, limited solubility, and rapid elimination. Cell-penetrating peptides (CPPs) covalently attached to PNAs may facilitate clinical development by improving uptake into cells. We report an efficient technology that utilizes a fully automated fast-flow instrument to manufacture CPP-conjugated PNAs (PPNAs) in a single shot. The machine is rapid, with each amide bond being formed in 10 s. Anti-IVS2-654 PPNA synthesized with this instrument presented threefold activity compared to transfected PNA in a splice-correction assay. We demonstrated the utility of this approach by chemically synthesizing eight anti-SARS-CoV-2 PPNAs in 1 day. A PPNA targeting the 5′ untranslated region of SARS-CoV-2 genomic RNA reduced the viral titer by over 95% in a live virus infection assay (IC(50) = 0.8 μM). Our technology can deliver PPNA candidates to further investigate their potential as antiviral agents. American Chemical Society 2021-11-15 2022-02-23 /pmc/articles/PMC8874765/ /pubmed/35233452 http://dx.doi.org/10.1021/acscentsci.1c01019 Text en © 2021 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 | Li, Chengxi Callahan, Alex J. Phadke, Kruttika S. Bellaire, Bryan Farquhar, Charlotte E. Zhang, Genwei Schissel, Carly K. Mijalis, Alexander J. Hartrampf, Nina Loas, Andrei Verhoeven, David E. Pentelute, Bradley L. Automated Flow Synthesis of Peptide–PNA Conjugates |
title | Automated Flow Synthesis of Peptide–PNA Conjugates |
title_full | Automated Flow Synthesis of Peptide–PNA Conjugates |
title_fullStr | Automated Flow Synthesis of Peptide–PNA Conjugates |
title_full_unstemmed | Automated Flow Synthesis of Peptide–PNA Conjugates |
title_short | Automated Flow Synthesis of Peptide–PNA Conjugates |
title_sort | automated flow synthesis of peptide–pna conjugates |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8874765/ https://www.ncbi.nlm.nih.gov/pubmed/35233452 http://dx.doi.org/10.1021/acscentsci.1c01019 |
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