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Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display

Insulin-degrading enzyme (IDE) is an atypical zinc-metalloendopeptidase that hydrolyzes insulin and other intermediate-sized peptide hormones, many of which are implicated in skin health and wound healing. Pharmacological inhibitors of IDE administered internally have been shown to slow the breakdow...

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Autores principales: Suire, Caitlin N., Nainar, Sarah, Fazio, Michael, Kreutzer, Adam G., Paymozd-Yazdi, Tara, Topper, Caitlyn L., Thompson, Caroline R., Leissring, Malcolm A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814047/
https://www.ncbi.nlm.nih.gov/pubmed/29447281
http://dx.doi.org/10.1371/journal.pone.0193101
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author Suire, Caitlin N.
Nainar, Sarah
Fazio, Michael
Kreutzer, Adam G.
Paymozd-Yazdi, Tara
Topper, Caitlyn L.
Thompson, Caroline R.
Leissring, Malcolm A.
author_facet Suire, Caitlin N.
Nainar, Sarah
Fazio, Michael
Kreutzer, Adam G.
Paymozd-Yazdi, Tara
Topper, Caitlyn L.
Thompson, Caroline R.
Leissring, Malcolm A.
author_sort Suire, Caitlin N.
collection PubMed
description Insulin-degrading enzyme (IDE) is an atypical zinc-metalloendopeptidase that hydrolyzes insulin and other intermediate-sized peptide hormones, many of which are implicated in skin health and wound healing. Pharmacological inhibitors of IDE administered internally have been shown to slow the breakdown of insulin and thereby potentiate insulin action. Given the importance of insulin and other IDE substrates for a variety of dermatological processes, pharmacological inhibitors of IDE suitable for topical applications would be expected to hold significant therapeutic and cosmetic potential. Existing IDE inhibitors, however, are prohibitively expensive, difficult to synthesize and of undetermined toxicity. Here we used phage display to discover novel peptidic inhibitors of IDE, which were subsequently characterized in vitro and in cell culture assays. Among several peptide sequences tested, a cyclic dodecapeptide dubbed P12-3A was found to potently inhibit the degradation of insulin (K(i) = 2.5 ± 0.31 μM) and other substrates by IDE, while also being resistant to degradation, stable in biological milieu, and highly selective for IDE. In cell culture, P12-3A was shown to potentiate several insulin-induced processes, including the transcription, translation and secretion of alpha-1 type I collagen in primary murine skin fibroblasts, and the migration of keratinocytes in a scratch wound migration assay. By virtue of its potency, stability, specificity for IDE, low cost of synthesis, and demonstrated ability to potentiate insulin-induced processes involved in wound healing and skin health, P12-3A holds significant therapeutic and cosmetic potential for topical applications.
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spelling pubmed-58140472018-03-02 Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display Suire, Caitlin N. Nainar, Sarah Fazio, Michael Kreutzer, Adam G. Paymozd-Yazdi, Tara Topper, Caitlyn L. Thompson, Caroline R. Leissring, Malcolm A. PLoS One Research Article Insulin-degrading enzyme (IDE) is an atypical zinc-metalloendopeptidase that hydrolyzes insulin and other intermediate-sized peptide hormones, many of which are implicated in skin health and wound healing. Pharmacological inhibitors of IDE administered internally have been shown to slow the breakdown of insulin and thereby potentiate insulin action. Given the importance of insulin and other IDE substrates for a variety of dermatological processes, pharmacological inhibitors of IDE suitable for topical applications would be expected to hold significant therapeutic and cosmetic potential. Existing IDE inhibitors, however, are prohibitively expensive, difficult to synthesize and of undetermined toxicity. Here we used phage display to discover novel peptidic inhibitors of IDE, which were subsequently characterized in vitro and in cell culture assays. Among several peptide sequences tested, a cyclic dodecapeptide dubbed P12-3A was found to potently inhibit the degradation of insulin (K(i) = 2.5 ± 0.31 μM) and other substrates by IDE, while also being resistant to degradation, stable in biological milieu, and highly selective for IDE. In cell culture, P12-3A was shown to potentiate several insulin-induced processes, including the transcription, translation and secretion of alpha-1 type I collagen in primary murine skin fibroblasts, and the migration of keratinocytes in a scratch wound migration assay. By virtue of its potency, stability, specificity for IDE, low cost of synthesis, and demonstrated ability to potentiate insulin-induced processes involved in wound healing and skin health, P12-3A holds significant therapeutic and cosmetic potential for topical applications. Public Library of Science 2018-02-15 /pmc/articles/PMC5814047/ /pubmed/29447281 http://dx.doi.org/10.1371/journal.pone.0193101 Text en © 2018 Suire et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Suire, Caitlin N.
Nainar, Sarah
Fazio, Michael
Kreutzer, Adam G.
Paymozd-Yazdi, Tara
Topper, Caitlyn L.
Thompson, Caroline R.
Leissring, Malcolm A.
Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display
title Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display
title_full Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display
title_fullStr Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display
title_full_unstemmed Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display
title_short Peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display
title_sort peptidic inhibitors of insulin-degrading enzyme with potential for dermatological applications discovered via phage display
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814047/
https://www.ncbi.nlm.nih.gov/pubmed/29447281
http://dx.doi.org/10.1371/journal.pone.0193101
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