Design of novel small molecule base-pair recognizers of toxic CUG RNA transcripts characteristics of DM1
Ondono, Raul (Universitat Ramon Llull. Institut Químic de Sarrià-IQS)
Lirio, Ángel (Universitat Ramon Llull. Institut Químic de Sarrià-IQS)
Elvira, Carlos ![Identificador ORCID](/img/uab/orcid.ico)
(Universitat Ramon Llull. Institut Químic de Sarrià-IQS)
Álvarez Marimon, Elena ![Identificador ORCID](/img/uab/orcid.ico)
(Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Provenzano, Claudia (Consiglio Nazionale delle Ricerche. Istituto di Biochimica e Biologia Cellulare)
Cardinali, Beatrice (Consiglio Nazionale delle Ricerche. Istituto di Biochimica e Biologia Cellulare)
Pérez-Alonso, Manuel (Universitat de València)
Peralvarez-Marin, Alex
(Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Borrell, José Ignacio (Universitat Ramon Llull. Institut Químic de Sarrià-IQS)
Falcone, Germana (Consiglio Nazionale delle Ricerche. Istituto di Biochimica e Biologia Cellulare)
Estrada-Tejedor, Roger (Universitat Ramon Llull. Institut Químic de Sarrià-IQS)
Data: |
2021 |
Resum: |
Myotonic Dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by toxic DMPK transcripts that carry CUG repeat expansions in the 3' untranslated region (3'UTR). The intrinsic complexity and lack of crystallographic data makes noncoding RNA regions challenging targets to study in the field of drug discovery. In DM1, toxic transcripts tend to stall in the nuclei forming complex inclusion bodies called foci and sequester many essential alternative splicing factors such as Muscleblind-like 1 (MBNL1). Most DM1 phenotypic features stem from the reduced availability of free MBNL1 and therefore many therapeutic efforts are focused on recovering its normal activity. For that purpose, herein we present pyrido[2,3- d ]pyrimidin-7-(8 H)-ones, a privileged scaffold showing remarkable biological activity against many targets involved in human disorders including cancer and viral diseases. Their combination with a flexible linker meets the requirements to stabilise DM1 toxic transcripts, and therefore, enabling the release of MBNL1. Therefore, a set of novel pyrido[2,3- d ]pyrimidin-7-(8 H)-ones derivatives (1a - e) were obtained using click chemistry. 1a exerted over 20% MBNL1 recovery on DM1 toxic RNA activity in primary cell biology studies using patient-derived myoblasts. 1a promising anti DM1 activity may lead to subsequent generations of ligands, highlighting a new affordable treatment against DM1. |
Ajuts: |
Instituto de Salud Carlos III FIS13-0386
|
Nota: |
Altres ajuts: Obra Social "La Caixa" |
Drets: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. ![Creative Commons](/img/licenses/by-nc-nd.ico) |
Llengua: |
Anglès |
Document: |
Article ; recerca ; Versió publicada |
Matèria: |
Myotonic dystrophy ;
Molecular modelling ;
RNA targeting ;
Small molecule ;
Base recognition |
Publicat a: |
Computational and Structural Biotechnology Journal, Vol. 19 (2021) , p. 51-61, ISSN 2001-0370 |
DOI: 10.1016/j.csbj.2020.11.053
PMID: 33363709
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Registre creat el 2021-04-12, darrera modificació el 2023-02-07