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VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects
Activity-dependent neuroprotective protein (ADNP) was discovered and first characterized in the laboratory of Prof. Illana Gozes to be regulated by vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) toward neuroprotection. Importantly, ADNP is a master re...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971164/ https://www.ncbi.nlm.nih.gov/pubmed/31992971 http://dx.doi.org/10.3389/fncel.2019.00589 |
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author | Sragovich, Shlomo Amram, Noy Yeheskel, Adva Gozes, Illana |
author_facet | Sragovich, Shlomo Amram, Noy Yeheskel, Adva Gozes, Illana |
author_sort | Sragovich, Shlomo |
collection | PubMed |
description | Activity-dependent neuroprotective protein (ADNP) was discovered and first characterized in the laboratory of Prof. Illana Gozes to be regulated by vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) toward neuroprotection. Importantly, ADNP is a master regulator of >400 genes, essential for brain formation, while its haploinsufficiency causes cognitive impairments. Recently, de novo mutations in ADNP were identified as leading to the autism-like ADNP syndrome, mimicked by the Adnp-deficient mouse model. Furthermore, novel peptide derivatives of the neuroprotective ADNP-snippet NAP (NAPVSIPQ), developed in our laboratory, include SKIP and the mirroring all D-amino acid SKIP (D-SKIP). We now extended previous evidence suggesting potential antagonistic features for D-SKIP, compared with the neuroprotective peptide SKIP, as was observed by NMR analysis and social/olfactory functional testing. Here, an impact of the Adnp genotype was observed in the Morris Water Maze (MWM) test measuring cognition, coupled with improvement by SKIP, opposing the inert/exacerbating effect of D-SKIP. In the elevated plus-maze and open field tests measuring anxiety-related behaviors, contrasting effects of SKIP and D-SKIP were found, with SKIP improving/preserving the normal phenotype of the mouse, and D-SKIP causing alterations. Lastly, an in silico analysis suggested that SKIP and D-SKIP bind the microtubule end binding (EB) proteins EB1 and EB3 in different conformations, thereby indicating distinctive natures for the two peptides, potentially mediating differential in vivo effects. Altogether, our findings corroborate the notion of D-SKIP acting as an antagonist, thus distinguishing it from the neuroprotective SKIP. |
format | Online Article Text |
id | pubmed-6971164 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69711642020-01-28 VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects Sragovich, Shlomo Amram, Noy Yeheskel, Adva Gozes, Illana Front Cell Neurosci Cellular Neuroscience Activity-dependent neuroprotective protein (ADNP) was discovered and first characterized in the laboratory of Prof. Illana Gozes to be regulated by vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) toward neuroprotection. Importantly, ADNP is a master regulator of >400 genes, essential for brain formation, while its haploinsufficiency causes cognitive impairments. Recently, de novo mutations in ADNP were identified as leading to the autism-like ADNP syndrome, mimicked by the Adnp-deficient mouse model. Furthermore, novel peptide derivatives of the neuroprotective ADNP-snippet NAP (NAPVSIPQ), developed in our laboratory, include SKIP and the mirroring all D-amino acid SKIP (D-SKIP). We now extended previous evidence suggesting potential antagonistic features for D-SKIP, compared with the neuroprotective peptide SKIP, as was observed by NMR analysis and social/olfactory functional testing. Here, an impact of the Adnp genotype was observed in the Morris Water Maze (MWM) test measuring cognition, coupled with improvement by SKIP, opposing the inert/exacerbating effect of D-SKIP. In the elevated plus-maze and open field tests measuring anxiety-related behaviors, contrasting effects of SKIP and D-SKIP were found, with SKIP improving/preserving the normal phenotype of the mouse, and D-SKIP causing alterations. Lastly, an in silico analysis suggested that SKIP and D-SKIP bind the microtubule end binding (EB) proteins EB1 and EB3 in different conformations, thereby indicating distinctive natures for the two peptides, potentially mediating differential in vivo effects. Altogether, our findings corroborate the notion of D-SKIP acting as an antagonist, thus distinguishing it from the neuroprotective SKIP. Frontiers Media S.A. 2020-01-14 /pmc/articles/PMC6971164/ /pubmed/31992971 http://dx.doi.org/10.3389/fncel.2019.00589 Text en Copyright © 2020 Sragovich, Amram, Yeheskel and Gozes. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular Neuroscience Sragovich, Shlomo Amram, Noy Yeheskel, Adva Gozes, Illana VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects |
title | VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects |
title_full | VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects |
title_fullStr | VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects |
title_full_unstemmed | VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects |
title_short | VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects |
title_sort | vip/pacap-based drug development: the adnp/nap-derived mirror peptides skip and d-skip exhibit distinctive in vivo and in silico effects |
topic | Cellular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971164/ https://www.ncbi.nlm.nih.gov/pubmed/31992971 http://dx.doi.org/10.3389/fncel.2019.00589 |
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