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DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid

Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structur...

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Autores principales: Oyaghire, Stanley N., Quijano, Elias, Perera, J. Dinithi R., Mandl, Hanna K., Saltzman, W. Mark, Bahal, Raman, Glazer, Peter M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621889/
https://www.ncbi.nlm.nih.gov/pubmed/37920723
http://dx.doi.org/10.1016/j.xcrp.2023.101635
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author Oyaghire, Stanley N.
Quijano, Elias
Perera, J. Dinithi R.
Mandl, Hanna K.
Saltzman, W. Mark
Bahal, Raman
Glazer, Peter M.
author_facet Oyaghire, Stanley N.
Quijano, Elias
Perera, J. Dinithi R.
Mandl, Hanna K.
Saltzman, W. Mark
Bahal, Raman
Glazer, Peter M.
author_sort Oyaghire, Stanley N.
collection PubMed
description Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structural modification poses a challenge because of the inherent racemization risk in O-alkylation of the precursory serine side chain. To circumvent this risk and improve γPNA accessibility, we explore the utility of γPNA oligomers possessing the hydroxymethyl-γ moiety for gene-editing applications. We demonstrate that a γPNA oligomer possessing the hydroxymethyl modification, despite weaker preorganization, retains the ability to form a hybrid with the double-stranded DNA target of comparable stability and with higher affinity than that of the diethylene glycol-γPNA. When formulated into poly(lactic-co-glycolic acid) nanoparticles, the hydroxymethyl-γPNA stimulates higher frequencies (≥ 1.5-fold) of gene modification than the diethylene glycol γPNA in mouse bone marrow cells.
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spelling pubmed-106218892023-11-02 DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid Oyaghire, Stanley N. Quijano, Elias Perera, J. Dinithi R. Mandl, Hanna K. Saltzman, W. Mark Bahal, Raman Glazer, Peter M. Cell Rep Phys Sci Article Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structural modification poses a challenge because of the inherent racemization risk in O-alkylation of the precursory serine side chain. To circumvent this risk and improve γPNA accessibility, we explore the utility of γPNA oligomers possessing the hydroxymethyl-γ moiety for gene-editing applications. We demonstrate that a γPNA oligomer possessing the hydroxymethyl modification, despite weaker preorganization, retains the ability to form a hybrid with the double-stranded DNA target of comparable stability and with higher affinity than that of the diethylene glycol-γPNA. When formulated into poly(lactic-co-glycolic acid) nanoparticles, the hydroxymethyl-γPNA stimulates higher frequencies (≥ 1.5-fold) of gene modification than the diethylene glycol γPNA in mouse bone marrow cells. 2023-10-18 /pmc/articles/PMC10621889/ /pubmed/37920723 http://dx.doi.org/10.1016/j.xcrp.2023.101635 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Oyaghire, Stanley N.
Quijano, Elias
Perera, J. Dinithi R.
Mandl, Hanna K.
Saltzman, W. Mark
Bahal, Raman
Glazer, Peter M.
DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid
title DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid
title_full DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid
title_fullStr DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid
title_full_unstemmed DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid
title_short DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid
title_sort dna recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621889/
https://www.ncbi.nlm.nih.gov/pubmed/37920723
http://dx.doi.org/10.1016/j.xcrp.2023.101635
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