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Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses

Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis(®) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentrat...

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Autores principales: Galant, Natalie J., Bugyei-Twum, Antoinette, Rakhit, Rishi, Walsh, Patrick, Sharpe, Simon, Arslan, Pharhad Eli, Westermark, Per, Higaki, Jeffrey N., Torres, Ronald, Tapia, José, Chakrabartty, Avijit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848561/
https://www.ncbi.nlm.nih.gov/pubmed/27122057
http://dx.doi.org/10.1038/srep25080
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author Galant, Natalie J.
Bugyei-Twum, Antoinette
Rakhit, Rishi
Walsh, Patrick
Sharpe, Simon
Arslan, Pharhad Eli
Westermark, Per
Higaki, Jeffrey N.
Torres, Ronald
Tapia, José
Chakrabartty, Avijit
author_facet Galant, Natalie J.
Bugyei-Twum, Antoinette
Rakhit, Rishi
Walsh, Patrick
Sharpe, Simon
Arslan, Pharhad Eli
Westermark, Per
Higaki, Jeffrey N.
Torres, Ronald
Tapia, José
Chakrabartty, Avijit
author_sort Galant, Natalie J.
collection PubMed
description Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis(®) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89–97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.
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spelling pubmed-48485612016-05-05 Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses Galant, Natalie J. Bugyei-Twum, Antoinette Rakhit, Rishi Walsh, Patrick Sharpe, Simon Arslan, Pharhad Eli Westermark, Per Higaki, Jeffrey N. Torres, Ronald Tapia, José Chakrabartty, Avijit Sci Rep Article Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis(®) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89–97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential. Nature Publishing Group 2016-04-28 /pmc/articles/PMC4848561/ /pubmed/27122057 http://dx.doi.org/10.1038/srep25080 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Galant, Natalie J.
Bugyei-Twum, Antoinette
Rakhit, Rishi
Walsh, Patrick
Sharpe, Simon
Arslan, Pharhad Eli
Westermark, Per
Higaki, Jeffrey N.
Torres, Ronald
Tapia, José
Chakrabartty, Avijit
Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses
title Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses
title_full Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses
title_fullStr Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses
title_full_unstemmed Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses
title_short Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses
title_sort substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for ttr amyloidoses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848561/
https://www.ncbi.nlm.nih.gov/pubmed/27122057
http://dx.doi.org/10.1038/srep25080
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