A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders

In the last two decades, abnormal Ras (rat sarcoma protein)–ERK (extracellular signal-regulated kinase) signalling in the brain has been involved in a variety of neuropsychiatric disorders, including drug addiction, certain forms of intellectual disability, and autism spectrum disorder. Modulation o...

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Autores principales:	Maria Rita Gulotta, Riccardo Brambilla, Ugo Perricone, Andrea Brancale
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Ras RasGRF1 hydrogen-bond surrogate computational residue scanning molecular dynamics MM-GBSA Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/4557875779384e07be7552d6eaf77b9a
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spelling	oai:doaj.org-article:4557875779384e07be7552d6eaf77b9a2021-11-25T18:39:19ZA Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders10.3390/ph141110991424-8247https://doaj.org/article/4557875779384e07be7552d6eaf77b9a2021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1099https://doaj.org/toc/1424-8247In the last two decades, abnormal Ras (rat sarcoma protein)–ERK (extracellular signal-regulated kinase) signalling in the brain has been involved in a variety of neuropsychiatric disorders, including drug addiction, certain forms of intellectual disability, and autism spectrum disorder. Modulation of membrane-receptor-mediated Ras activation has been proposed as a potential target mechanism to attenuate ERK signalling in the brain. Previously, we showed that a cell penetrating peptide, RB3, was able to inhibit downstream signalling by preventing RasGRF1 (Ras guanine nucleotide-releasing factor 1), a neuronal specific GDP/GTP exchange factor, to bind Ras proteins, both in brain slices and in vivo, with an IC<sub>50</sub> value in the micromolar range. The aim of this work was to mutate and improve this peptide through computer-aided techniques to increase its inhibitory activity against RasGRF1. The designed peptides were built based on the RB3 peptide structure corresponding to the α-helix of RasGRF1 responsible for Ras binding. For this purpose, the hydrogen-bond surrogate (HBS) approach was exploited to maintain the helical conformation of the designed peptides. Finally, residue scanning, MD simulations, and MM-GBSA calculations were used to identify 18 most promising α-helix-shaped peptides that will be assayed to check their potential activity against Ras-RasGRF1 and prevent downstream molecular events implicated in brain disorders.Maria Rita GulottaRiccardo BrambillaUgo PerriconeAndrea BrancaleMDPI AGarticleRasRasGRF1hydrogen-bond surrogatecomputational residue scanningmolecular dynamicsMM-GBSAMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1099, p 1099 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Ras RasGRF1 hydrogen-bond surrogate computational residue scanning molecular dynamics MM-GBSA Medicine R Pharmacy and materia medica RS1-441
spellingShingle	Ras RasGRF1 hydrogen-bond surrogate computational residue scanning molecular dynamics MM-GBSA Medicine R Pharmacy and materia medica RS1-441 Maria Rita Gulotta Riccardo Brambilla Ugo Perricone Andrea Brancale A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders
description	In the last two decades, abnormal Ras (rat sarcoma protein)–ERK (extracellular signal-regulated kinase) signalling in the brain has been involved in a variety of neuropsychiatric disorders, including drug addiction, certain forms of intellectual disability, and autism spectrum disorder. Modulation of membrane-receptor-mediated Ras activation has been proposed as a potential target mechanism to attenuate ERK signalling in the brain. Previously, we showed that a cell penetrating peptide, RB3, was able to inhibit downstream signalling by preventing RasGRF1 (Ras guanine nucleotide-releasing factor 1), a neuronal specific GDP/GTP exchange factor, to bind Ras proteins, both in brain slices and in vivo, with an IC<sub>50</sub> value in the micromolar range. The aim of this work was to mutate and improve this peptide through computer-aided techniques to increase its inhibitory activity against RasGRF1. The designed peptides were built based on the RB3 peptide structure corresponding to the α-helix of RasGRF1 responsible for Ras binding. For this purpose, the hydrogen-bond surrogate (HBS) approach was exploited to maintain the helical conformation of the designed peptides. Finally, residue scanning, MD simulations, and MM-GBSA calculations were used to identify 18 most promising α-helix-shaped peptides that will be assayed to check their potential activity against Ras-RasGRF1 and prevent downstream molecular events implicated in brain disorders.
format	article
author	Maria Rita Gulotta Riccardo Brambilla Ugo Perricone Andrea Brancale
author_facet	Maria Rita Gulotta Riccardo Brambilla Ugo Perricone Andrea Brancale
author_sort	Maria Rita Gulotta
title	A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders
title_short	A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders
title_full	A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders
title_fullStr	A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders
title_full_unstemmed	A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders
title_sort	rational design of α-helix-shaped peptides employing the hydrogen-bond surrogate approach: a modulation strategy for ras-rasgrf1 interaction in neuropsychiatric disorders
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4557875779384e07be7552d6eaf77b9a
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A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders

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