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Bifunctional ligand design for modulating mutant p53 aggregation in cancer
Protein misfolding and aggregation contributes to the development of a wide range of diseases. In cancer, over 50% of diagnoses are attributed to p53 malfunction due to missense mutations, many of which result in protein misfolding and accelerated aggregation. p53 mutations also frequently result in...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006507/ https://www.ncbi.nlm.nih.gov/pubmed/32055386 http://dx.doi.org/10.1039/c9sc04151f |
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author | Miller, Jessica J. Blanchet, Anaïs Orvain, Christophe Nouchikian, Lucienne Reviriot, Yasmin Clarke, Ryan M. Martelino, Diego Wilson, Derek Gaiddon, Christian Storr, Tim |
author_facet | Miller, Jessica J. Blanchet, Anaïs Orvain, Christophe Nouchikian, Lucienne Reviriot, Yasmin Clarke, Ryan M. Martelino, Diego Wilson, Derek Gaiddon, Christian Storr, Tim |
author_sort | Miller, Jessica J. |
collection | PubMed |
description | Protein misfolding and aggregation contributes to the development of a wide range of diseases. In cancer, over 50% of diagnoses are attributed to p53 malfunction due to missense mutations, many of which result in protein misfolding and accelerated aggregation. p53 mutations also frequently result in alteration or loss of zinc at the DNA-binding site, which increases aggregation via nucleation with zinc-bound p53. Herein, we designed two novel bifunctional ligands, L(I) and L(H), to modulate mutant p53 aggregation and restore zinc binding using a metallochaperone approach. Interestingly, only the incorporation of iodine function in L(I) resulted in modulation of mutant p53 aggregation, both in recombinant and cellular environments. Native mass spectrometry shows a protein–ligand interaction for L(I), as opposed to L(H), which is hypothesized to lead to the distinct difference in the p53 aggregation profile for the two ligands. Incorporation of a di-2-picolylamine binding unit into the ligand design provided efficient intracellular zinc uptake, resulting in metallochaperone capability for both L(I) and L(H). The ability of L(I) to reduce mutant p53 aggregation results in increased restoration of p53 transcriptional function and mediates both caspase-dependent and -independent cell death pathways. We further demonstrate that L(I) exhibits minimal toxicity in non-cancerous organoids, and that it is well tolerated in mice. These results demonstrate that iodination of our ligand framework restores p53 function by interacting with and inhibiting mutant p53 aggregation and highlights L(I) as a suitable candidate for comprehensive in vivo anticancer preclinical evaluations. |
format | Online Article Text |
id | pubmed-7006507 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-70065072020-02-13 Bifunctional ligand design for modulating mutant p53 aggregation in cancer Miller, Jessica J. Blanchet, Anaïs Orvain, Christophe Nouchikian, Lucienne Reviriot, Yasmin Clarke, Ryan M. Martelino, Diego Wilson, Derek Gaiddon, Christian Storr, Tim Chem Sci Chemistry Protein misfolding and aggregation contributes to the development of a wide range of diseases. In cancer, over 50% of diagnoses are attributed to p53 malfunction due to missense mutations, many of which result in protein misfolding and accelerated aggregation. p53 mutations also frequently result in alteration or loss of zinc at the DNA-binding site, which increases aggregation via nucleation with zinc-bound p53. Herein, we designed two novel bifunctional ligands, L(I) and L(H), to modulate mutant p53 aggregation and restore zinc binding using a metallochaperone approach. Interestingly, only the incorporation of iodine function in L(I) resulted in modulation of mutant p53 aggregation, both in recombinant and cellular environments. Native mass spectrometry shows a protein–ligand interaction for L(I), as opposed to L(H), which is hypothesized to lead to the distinct difference in the p53 aggregation profile for the two ligands. Incorporation of a di-2-picolylamine binding unit into the ligand design provided efficient intracellular zinc uptake, resulting in metallochaperone capability for both L(I) and L(H). The ability of L(I) to reduce mutant p53 aggregation results in increased restoration of p53 transcriptional function and mediates both caspase-dependent and -independent cell death pathways. We further demonstrate that L(I) exhibits minimal toxicity in non-cancerous organoids, and that it is well tolerated in mice. These results demonstrate that iodination of our ligand framework restores p53 function by interacting with and inhibiting mutant p53 aggregation and highlights L(I) as a suitable candidate for comprehensive in vivo anticancer preclinical evaluations. Royal Society of Chemistry 2019-10-07 /pmc/articles/PMC7006507/ /pubmed/32055386 http://dx.doi.org/10.1039/c9sc04151f Text en This journal is © The Royal Society of Chemistry 2019 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0) |
spellingShingle | Chemistry Miller, Jessica J. Blanchet, Anaïs Orvain, Christophe Nouchikian, Lucienne Reviriot, Yasmin Clarke, Ryan M. Martelino, Diego Wilson, Derek Gaiddon, Christian Storr, Tim Bifunctional ligand design for modulating mutant p53 aggregation in cancer |
title | Bifunctional ligand design for modulating mutant p53 aggregation in cancer
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title_full | Bifunctional ligand design for modulating mutant p53 aggregation in cancer
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title_fullStr | Bifunctional ligand design for modulating mutant p53 aggregation in cancer
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title_full_unstemmed | Bifunctional ligand design for modulating mutant p53 aggregation in cancer
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title_short | Bifunctional ligand design for modulating mutant p53 aggregation in cancer
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title_sort | bifunctional ligand design for modulating mutant p53 aggregation in cancer |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006507/ https://www.ncbi.nlm.nih.gov/pubmed/32055386 http://dx.doi.org/10.1039/c9sc04151f |
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