A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders.
Maria Rita GulottaRiccardo BrambillaPerricone UgoAndrea BrancalePublished in: Pharmaceuticals (Basel, Switzerland) (2021)
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.
Keyphrases
- wild type
- autism spectrum disorder
- intellectual disability
- resting state
- white matter
- amino acid
- cerebral ischemia
- signaling pathway
- molecular dynamics
- functional connectivity
- dna binding
- oxidative stress
- cell therapy
- stem cells
- molecular dynamics simulations
- small molecule
- transcription factor
- attention deficit hyperactivity disorder
- density functional theory
- brain injury
- human health
- emergency department
- binding protein
- mass spectrometry
- subarachnoid hemorrhage
- pi k akt
- single molecule
- working memory
- protein kinase
- transition metal