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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

Gulotta, Maria Rita, Brambilla, Riccardo, Perricone, Ugo and Brancale, Andrea 2021. A rational design of α-helix-shaped peptides employing the hydrogen-bond surrogate approach: A modulation strategy for Ras-RasGRF1 interaction in neuropsychiatric disorders. Pharmaceuticals 14 (11) , 1099. 10.3390/ph14111099

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Abstract

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 IC50 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Pharmacy
Additional Information: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Publisher: MDPI
ISSN: 1424-8247
Date of First Compliant Deposit: 1 November 2021
Date of Acceptance: 26 October 2021
Last Modified: 04 Nov 2021 10:30
URI: https://orca.cardiff.ac.uk/id/eprint/145228

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