Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we report a computational study to identify new TRID scaffolds. A pharmacophore approach was carried out on compounds that showed readthrough activity. The pharmacophore model applied to screen different libraries containing more than 87000 compounds identified four hit-compounds presenting scaffolds with diversity from the oxadiazole lead. These compounds have been synthesized and tested using the Fluc reporter harboring the UGA PTC. Moreover, the cytotoxic effect and the expression of the CFTR protein were evaluated. These compounds, a benzimidazole derivative (NV2899), a benzoxazole derivative (NV2913), a thiazole derivative (NV2909), and a benzene-1,3-disulfonate derivative (NV2907), were shown to be potential new lead compounds as TRIDs, boosting further efforts to address the optimization of the chemical scaffolds.

Tutone M., Pibiri I., Perriera R., Campofelice A., Culletta G., Melfi R., et al. (2020). Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs). ACS MEDICINAL CHEMISTRY LETTERS, 11(5), 747-753 [10.1021/acsmedchemlett.9b00609].

Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs)

Tutone M.
;
Pibiri I.
;
Perriera R.;Campofelice A.;Culletta G.;Melfi R.;Pace A.;Almerico A. M.;Lentini L.
2020

Abstract

Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we report a computational study to identify new TRID scaffolds. A pharmacophore approach was carried out on compounds that showed readthrough activity. The pharmacophore model applied to screen different libraries containing more than 87000 compounds identified four hit-compounds presenting scaffolds with diversity from the oxadiazole lead. These compounds have been synthesized and tested using the Fluc reporter harboring the UGA PTC. Moreover, the cytotoxic effect and the expression of the CFTR protein were evaluated. These compounds, a benzimidazole derivative (NV2899), a benzoxazole derivative (NV2913), a thiazole derivative (NV2909), and a benzene-1,3-disulfonate derivative (NV2907), were shown to be potential new lead compounds as TRIDs, boosting further efforts to address the optimization of the chemical scaffolds.
Tutone M., Pibiri I., Perriera R., Campofelice A., Culletta G., Melfi R., et al. (2020). Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs). ACS MEDICINAL CHEMISTRY LETTERS, 11(5), 747-753 [10.1021/acsmedchemlett.9b00609].
File in questo prodotto:
File Dimensione Formato  
draft_Proof_hi.pdf

Solo gestori archvio

Descrizione: Articolo principale
Tipologia: Pre-print
Dimensione 582.44 kB
Formato Adobe PDF
582.44 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
acsmedchemlett.9b00609.pdf

Solo gestori archvio

Descrizione: Articolo principale
Tipologia: Versione Editoriale
Dimensione 7.43 MB
Formato Adobe PDF
7.43 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/427087
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 5
social impact