Targeting SHP2 and Sos1 to block Noonan Syndrome

Anno
2021
Proponente Caterina Nardella - Assegnista di ricerca
Sottosettore ERC del proponente del progetto
LS1_1
Componenti gruppo di ricerca
Componente Categoria
Stefano Gianni Aggiungi Tutor di riferimento (Professore o Ricercatore afferente allo stesso Dipartimento del Proponente)
Abstract

Noonan Syndrome (NS, OMIM 163950) is a condition characterized by typical craniofacial abnormalities, congenital cardiac defects, pulmonic stenosis, a wide spectrum of cognitive disorders causing a wide spectrum of mild/moderate mental retardation and learning disabilities (ranging from attention deficits to language impairments), multiple skeletal defects, cryptorchidism, short stature. More than 50% of the NS cases are caused by mutations in the PTPN11 gene, and 10-20% of the cases by mutations on SOS1 gene, encoding for two proteins, SHP2 and SOS1 respectively, that possess critical roles in the activation and regulation of the RAS/MAPK pathway. In both cases, mutations result in an abnormal gain-of-function, with mutations insisting on residues maintaining the proteins in an auto-inhibited state for SHP2 and mutations strengthening the interaction with Grb2 in the case of SOS1.
The project is based on the hypothesis that an effective therapeutic strategy for NS would be based on the recovery of the SHP2 and SOS1 normal functions. This aim will be achieved by studying the mechanisms of activation of SHP2 and SOS1 and designing small molecules to hijack the functions of these two proteins in the naturally occurring NS mutants.
The experimental plan is, therefore, based on the synergy between experimental and computational techniques focused on the understanding of the molecular details of the gain-of-function of SHP2 and SOS1 in NS. In parallel, small molecules stabilizing the auto-inhibited state of the two proteins will be selected via virtual screening and, subsequently, studied in vitro.
Overall, the proposed project has the goal to provide a mechanistic characterization of the most prominent mutations associated with NS and to identify one or more lead compound aimed at reducing the gain-of-function observed in the pathological conditions.

ERC
LS1_1, LS1_2, LS1_8
Keywords:
CHIMICA FISICA DEI SISTEMI BIOLOGICI, APPLICAZIONI BIOLOGICHE DELLA FISICA, BIOCHIMICA, PROTEINE RICOMBINANTI, BIOLOGIA MOLECOLARE E INTERAZIONI

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