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Design and Synthesis of Oligopeptidic Parvulin Inhibitors
Pin1 catalyzes the cis‐trans isomerization of pThr‐Pro or pSer‐Pro amide bonds of various proteins involved in several physio/pathological processes. In this framework, recent research activity is directed toward the identification of new selective Pin1 inhibitors. Here, we developed a set of peptid...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9321596/ https://www.ncbi.nlm.nih.gov/pubmed/35357776 http://dx.doi.org/10.1002/cmdc.202200050 |
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author | Relitti, Nicola Prasanth Saraswati, A. Carullo, Gabriele Papa, Alessandro Monti, Alessandra Benedetti, Rosaria Passaro, Eugenia Brogi, Simone Calderone, Vincenzo Butini, Stefania Gemma, Sandra Altucci, Lucia Campiani, Giuseppe Doti, Nunzianna |
author_facet | Relitti, Nicola Prasanth Saraswati, A. Carullo, Gabriele Papa, Alessandro Monti, Alessandra Benedetti, Rosaria Passaro, Eugenia Brogi, Simone Calderone, Vincenzo Butini, Stefania Gemma, Sandra Altucci, Lucia Campiani, Giuseppe Doti, Nunzianna |
author_sort | Relitti, Nicola |
collection | PubMed |
description | Pin1 catalyzes the cis‐trans isomerization of pThr‐Pro or pSer‐Pro amide bonds of various proteins involved in several physio/pathological processes. In this framework, recent research activity is directed toward the identification of new selective Pin1 inhibitors. Here, we developed a set of peptide‐based Pin1 inhibitors. Direct‐binding experiments allowed the identification of the peptide‐based inhibitor 5 k (methylacetyl‐l‐alanyl‐l‐histidyl‐l‐prolyl‐l‐phenylalaninate) as a potent ligand of Pin1. Notably, 5 k binds Pin1 with higher affinity than Pin4. The comparative analysis of molecular models of Pin1 and Pin4 with the selected compound gave a rational explanation of the biochemical activity and pinpointed the chemical elements that, if opportunely modified, may further improve inhibitory potency, pharmacological properties, and selectivity of future peptide‐based parvulin inhibitors. Since 5 k showed limited cell penetration and no antiproliferative activity, it was conjugated to a polyarginine stretch (R8), known to promote cell penetration of peptides, to obtain the R8–5 k derivative, which displayed antiproliferative effects on cancer cell lines over non‐tumor cells. The effect of R8 on cell proliferation was also investigated. This work warrants caution about applying the R8 strategy in the development of cell‐penetrating antiproliferative peptides, as it is not inert. |
format | Online Article Text |
id | pubmed-9321596 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93215962022-07-30 Design and Synthesis of Oligopeptidic Parvulin Inhibitors Relitti, Nicola Prasanth Saraswati, A. Carullo, Gabriele Papa, Alessandro Monti, Alessandra Benedetti, Rosaria Passaro, Eugenia Brogi, Simone Calderone, Vincenzo Butini, Stefania Gemma, Sandra Altucci, Lucia Campiani, Giuseppe Doti, Nunzianna ChemMedChem Research Articles Pin1 catalyzes the cis‐trans isomerization of pThr‐Pro or pSer‐Pro amide bonds of various proteins involved in several physio/pathological processes. In this framework, recent research activity is directed toward the identification of new selective Pin1 inhibitors. Here, we developed a set of peptide‐based Pin1 inhibitors. Direct‐binding experiments allowed the identification of the peptide‐based inhibitor 5 k (methylacetyl‐l‐alanyl‐l‐histidyl‐l‐prolyl‐l‐phenylalaninate) as a potent ligand of Pin1. Notably, 5 k binds Pin1 with higher affinity than Pin4. The comparative analysis of molecular models of Pin1 and Pin4 with the selected compound gave a rational explanation of the biochemical activity and pinpointed the chemical elements that, if opportunely modified, may further improve inhibitory potency, pharmacological properties, and selectivity of future peptide‐based parvulin inhibitors. Since 5 k showed limited cell penetration and no antiproliferative activity, it was conjugated to a polyarginine stretch (R8), known to promote cell penetration of peptides, to obtain the R8–5 k derivative, which displayed antiproliferative effects on cancer cell lines over non‐tumor cells. The effect of R8 on cell proliferation was also investigated. This work warrants caution about applying the R8 strategy in the development of cell‐penetrating antiproliferative peptides, as it is not inert. John Wiley and Sons Inc. 2022-04-26 2022-06-03 /pmc/articles/PMC9321596/ /pubmed/35357776 http://dx.doi.org/10.1002/cmdc.202200050 Text en © 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Relitti, Nicola Prasanth Saraswati, A. Carullo, Gabriele Papa, Alessandro Monti, Alessandra Benedetti, Rosaria Passaro, Eugenia Brogi, Simone Calderone, Vincenzo Butini, Stefania Gemma, Sandra Altucci, Lucia Campiani, Giuseppe Doti, Nunzianna Design and Synthesis of Oligopeptidic Parvulin Inhibitors |
title | Design and Synthesis of Oligopeptidic Parvulin Inhibitors |
title_full | Design and Synthesis of Oligopeptidic Parvulin Inhibitors |
title_fullStr | Design and Synthesis of Oligopeptidic Parvulin Inhibitors |
title_full_unstemmed | Design and Synthesis of Oligopeptidic Parvulin Inhibitors |
title_short | Design and Synthesis of Oligopeptidic Parvulin Inhibitors |
title_sort | design and synthesis of oligopeptidic parvulin inhibitors |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9321596/ https://www.ncbi.nlm.nih.gov/pubmed/35357776 http://dx.doi.org/10.1002/cmdc.202200050 |
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