Automated Flow Synthesis of Peptide–PNA Conjugates
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 efficie...
| Main Authors: | , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Chemical Society (ACS)
2022
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| Online Access: | https://hdl.handle.net/1721.1/141205 |
| _version_ | 1810987097018859520 |
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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 |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry 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 | MIT |
| description | 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 (IC50 = 0.8 μM). Our technology can deliver PPNA candidates to further investigate their potential as antiviral agents. |
| first_indexed | 2024-09-23T11:44:41Z |
| format | Article |
| id | mit-1721.1/141205 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:44:41Z |
| publishDate | 2022 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1412052023-02-09T18:59:15Z 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 Massachusetts Institute of Technology. Department of Chemistry 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 (IC50 = 0.8 μM). Our technology can deliver PPNA candidates to further investigate their potential as antiviral agents. 2022-03-15T19:07:21Z 2022-03-15T19:07:21Z 2022-02-23 2022-03-15T19:04:32Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/141205 Li, Chengxi, Callahan, Alex J, Phadke, Kruttika S, Bellaire, Bryan, Farquhar, Charlotte E et al. 2022. "Automated Flow Synthesis of Peptide–PNA Conjugates." ACS Central Science, 8 (2). en 10.1021/acscentsci.1c01019 ACS Central Science Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf American Chemical Society (ACS) ACS |
| 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://hdl.handle.net/1721.1/141205 |
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