Identification of a new molecule with readthrough activity to rescue CFTR protein function

Risultato della ricerca: Other

Abstract

In Cystic fibrosis (CF) disease nonsense mutations in the CFTR gene cause absence of the CFTR protein expression and a more severe form of the disease. About 10% of patient affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by translational readthrough inducing drugs such as Ataluren. In this context we aimed to compare the 1,2,4-oxadiazole core of Ataluren with a slightly different scaffold, the 1,3,4oxadiazole core. By a validated protocol consisting of computational screening, synthesis and biological tests we identified, a new small molecule with 1,3,4-oxadiazole core (2a/NV2445) showing high readthrough activity. Moreover, we evaluated quantitatively the CFTR functionality after 2a/NV2445 treatment in CF model systems and in cells expressing a nonsense-CFTR-mRNA. Finally, we studied the supramolecular interactions among readthrough inducing drugs and CFTR mRNA to assess the biological target/mechanism and further we used the QikProp program to compare the ADME properties of 2a/NV2445 and Ataluren.
Lingua originaleEnglish
Numero di pagine2
Stato di pubblicazionePublished - 2018

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Nonsense Codon
Cystic Fibrosis
Oxadiazoles
Messenger RNA
Pharmaceutical Preparations
Therapeutics
Genes
ataluren

Cita questo

@conference{ca88f63effc44428ac51aa74e3945f29,
title = "Identification of a new molecule with readthrough activity to rescue CFTR protein function",
abstract = "In Cystic fibrosis (CF) disease nonsense mutations in the CFTR gene cause absence of the CFTR protein expression and a more severe form of the disease. About 10{\%} of patient affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by translational readthrough inducing drugs such as Ataluren. In this context we aimed to compare the 1,2,4-oxadiazole core of Ataluren with a slightly different scaffold, the 1,3,4oxadiazole core. By a validated protocol consisting of computational screening, synthesis and biological tests we identified, a new small molecule with 1,3,4-oxadiazole core (2a/NV2445) showing high readthrough activity. Moreover, we evaluated quantitatively the CFTR functionality after 2a/NV2445 treatment in CF model systems and in cells expressing a nonsense-CFTR-mRNA. Finally, we studied the supramolecular interactions among readthrough inducing drugs and CFTR mRNA to assess the biological target/mechanism and further we used the QikProp program to compare the ADME properties of 2a/NV2445 and Ataluren.",
keywords = "CFTR, Cystic fibrosis, oxadiazoles, readthrough",
author = "Andrea Pace and Laura Lentini and Marco Tutone and Ivana Pibiri and Raffaella Melfi and {Di Leonardo}, Aldo and Sara Baldassano and {Ricco Galluzzo}, Paola",
year = "2018",
language = "English",

}

TY - CONF

T1 - Identification of a new molecule with readthrough activity to rescue CFTR protein function

AU - Pace, Andrea

AU - Lentini, Laura

AU - Tutone, Marco

AU - Pibiri, Ivana

AU - Melfi, Raffaella

AU - Di Leonardo, Aldo

AU - Baldassano, Sara

AU - Ricco Galluzzo, Paola

PY - 2018

Y1 - 2018

N2 - In Cystic fibrosis (CF) disease nonsense mutations in the CFTR gene cause absence of the CFTR protein expression and a more severe form of the disease. About 10% of patient affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by translational readthrough inducing drugs such as Ataluren. In this context we aimed to compare the 1,2,4-oxadiazole core of Ataluren with a slightly different scaffold, the 1,3,4oxadiazole core. By a validated protocol consisting of computational screening, synthesis and biological tests we identified, a new small molecule with 1,3,4-oxadiazole core (2a/NV2445) showing high readthrough activity. Moreover, we evaluated quantitatively the CFTR functionality after 2a/NV2445 treatment in CF model systems and in cells expressing a nonsense-CFTR-mRNA. Finally, we studied the supramolecular interactions among readthrough inducing drugs and CFTR mRNA to assess the biological target/mechanism and further we used the QikProp program to compare the ADME properties of 2a/NV2445 and Ataluren.

AB - In Cystic fibrosis (CF) disease nonsense mutations in the CFTR gene cause absence of the CFTR protein expression and a more severe form of the disease. About 10% of patient affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by translational readthrough inducing drugs such as Ataluren. In this context we aimed to compare the 1,2,4-oxadiazole core of Ataluren with a slightly different scaffold, the 1,3,4oxadiazole core. By a validated protocol consisting of computational screening, synthesis and biological tests we identified, a new small molecule with 1,3,4-oxadiazole core (2a/NV2445) showing high readthrough activity. Moreover, we evaluated quantitatively the CFTR functionality after 2a/NV2445 treatment in CF model systems and in cells expressing a nonsense-CFTR-mRNA. Finally, we studied the supramolecular interactions among readthrough inducing drugs and CFTR mRNA to assess the biological target/mechanism and further we used the QikProp program to compare the ADME properties of 2a/NV2445 and Ataluren.

KW - CFTR

KW - Cystic fibrosis

KW - oxadiazoles

KW - readthrough

UR - http://hdl.handle.net/10447/350040

M3 - Other

ER -