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A transcytotic transport mechanism across the tympanic membrane
Drug treatments for middle ear diseases are currently delivered systemically, or locally after opening the impermeable tympanic membrane (TM). We previously used bacteriophage display to discover novel peptides that are actively transported across the intact TM, with a variety of transport rates. Pe...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770641/ https://www.ncbi.nlm.nih.gov/pubmed/35046419 http://dx.doi.org/10.1038/s41598-021-04748-w |
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author | Kurabi, Arwa Pak, Kwang Chavez, Eduardo Doan, Jennifer Ryan, Allen F. |
author_facet | Kurabi, Arwa Pak, Kwang Chavez, Eduardo Doan, Jennifer Ryan, Allen F. |
author_sort | Kurabi, Arwa |
collection | PubMed |
description | Drug treatments for middle ear diseases are currently delivered systemically, or locally after opening the impermeable tympanic membrane (TM). We previously used bacteriophage display to discover novel peptides that are actively transported across the intact TM, with a variety of transport rates. Peptide structures were analyzed for evidence regarding the mechanism for this unexpected transport, which was then tested by the application of chemical inhibitors. Primary sequences indicated that trans-TM peptides share one of two amino acid motifs. Secondary structures revealed that linear configurations associate with higher transport rates than coiled structures. Tertiary analysis indicated that the shared sequence motifs are prominently displayed at the free ends of rapidly transported peptide phage. The shared motifs were evaluated for similarity to known motifs. The highest probability matches were for protein motifs involved in transmembrane transport and exosomes. Overall, structural findings suggest that the shared motifs represent binding sequences. They also implicate transcytosis, a polarized cell transport mechanism consisting of endocytosis, transcellular transport, and exocytosis. Inhibitor studies indicated that macropinocytosis, retrograde transport through Golgi and exocytosis participate in transport across the TM, consistent with transcytosis. This process can be harnessed to noninvasively deliver therapeutics to the middle ear. |
format | Online Article Text |
id | pubmed-8770641 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87706412022-01-24 A transcytotic transport mechanism across the tympanic membrane Kurabi, Arwa Pak, Kwang Chavez, Eduardo Doan, Jennifer Ryan, Allen F. Sci Rep Article Drug treatments for middle ear diseases are currently delivered systemically, or locally after opening the impermeable tympanic membrane (TM). We previously used bacteriophage display to discover novel peptides that are actively transported across the intact TM, with a variety of transport rates. Peptide structures were analyzed for evidence regarding the mechanism for this unexpected transport, which was then tested by the application of chemical inhibitors. Primary sequences indicated that trans-TM peptides share one of two amino acid motifs. Secondary structures revealed that linear configurations associate with higher transport rates than coiled structures. Tertiary analysis indicated that the shared sequence motifs are prominently displayed at the free ends of rapidly transported peptide phage. The shared motifs were evaluated for similarity to known motifs. The highest probability matches were for protein motifs involved in transmembrane transport and exosomes. Overall, structural findings suggest that the shared motifs represent binding sequences. They also implicate transcytosis, a polarized cell transport mechanism consisting of endocytosis, transcellular transport, and exocytosis. Inhibitor studies indicated that macropinocytosis, retrograde transport through Golgi and exocytosis participate in transport across the TM, consistent with transcytosis. This process can be harnessed to noninvasively deliver therapeutics to the middle ear. Nature Publishing Group UK 2022-01-19 /pmc/articles/PMC8770641/ /pubmed/35046419 http://dx.doi.org/10.1038/s41598-021-04748-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kurabi, Arwa Pak, Kwang Chavez, Eduardo Doan, Jennifer Ryan, Allen F. A transcytotic transport mechanism across the tympanic membrane |
title | A transcytotic transport mechanism across the tympanic membrane |
title_full | A transcytotic transport mechanism across the tympanic membrane |
title_fullStr | A transcytotic transport mechanism across the tympanic membrane |
title_full_unstemmed | A transcytotic transport mechanism across the tympanic membrane |
title_short | A transcytotic transport mechanism across the tympanic membrane |
title_sort | transcytotic transport mechanism across the tympanic membrane |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770641/ https://www.ncbi.nlm.nih.gov/pubmed/35046419 http://dx.doi.org/10.1038/s41598-021-04748-w |
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