Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation

Dinucleotide analogs of the messenger RNA cap (m<sup>7</sup>GpppN) are useful research tools and have potential applications as translational inhibitors or reagents for modification of in vitro transcribed mRNAs. It has been previously reported that replacing the methyl group at the N7-p...

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Autores principales:	Radoslaw Wojcik, Marek R. Baranowski, Lukasz Markiewicz, Dorota Kubacka, Marcelina Bednarczyk, Natalia Baran, Anna Wojtczak, Pawel J. Sikorski, Joanna Zuberek, Joanna Kowalska, Jacek Jemielity
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	transcription translation cap analogs mRNA eIF4E DcpS Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/31081b992c5141aa820199bd8e43fc38
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spelling	oai:doaj.org-article:31081b992c5141aa820199bd8e43fc382021-11-25T18:42:13ZNovel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation10.3390/pharmaceutics131119411999-4923https://doaj.org/article/31081b992c5141aa820199bd8e43fc382021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1941https://doaj.org/toc/1999-4923Dinucleotide analogs of the messenger RNA cap (m<sup>7</sup>GpppN) are useful research tools and have potential applications as translational inhibitors or reagents for modification of in vitro transcribed mRNAs. It has been previously reported that replacing the methyl group at the N7-position with benzyl (Bn) produces a dinucleotide cap with superior properties. Here, we followed up on this finding by synthesizing 17 novel Bn<sup>7</sup>GpppG analogs and determining their structure–activity relationship regarding translation and translational inhibition. The compounds were prepared in two steps, including selective N7-alkylation of guanosine 5′-monophosphate by arylmethyl bromide followed by coupling with imidazole-activated GDP, with total yields varying from 22% to 62%. The compounds were then evaluated by determining their affinity for eukaryotic translation initiation factor 4E (eIF4E), testing their susceptibility to decapping pyrophosphatase, DcpS—which is most likely the major cellular enzyme targeting this type of compound—and determining their translation inhibitory properties in vitro. We also synthesized mRNAs capped with the evaluated compounds and tested their translational properties in A549 cells. Our studies identified N7-(4-halogenbenzyl) substituents as promising modifications in the contexts of either mRNA translation or translational inhibition. Finally, to gain more insight into the consequences at the molecular level of N7-benzylation of the mRNA cap, we determined the crystal structures of three compounds with eIF4E.Radoslaw WojcikMarek R. BaranowskiLukasz MarkiewiczDorota KubackaMarcelina BednarczykNatalia BaranAnna WojtczakPawel J. SikorskiJoanna ZuberekJoanna KowalskaJacek JemielityMDPI AGarticletranscriptiontranslationcap analogsmRNAeIF4EDcpSPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1941, p 1941 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	transcription translation cap analogs mRNA eIF4E DcpS Pharmacy and materia medica RS1-441
spellingShingle	transcription translation cap analogs mRNA eIF4E DcpS Pharmacy and materia medica RS1-441 Radoslaw Wojcik Marek R. Baranowski Lukasz Markiewicz Dorota Kubacka Marcelina Bednarczyk Natalia Baran Anna Wojtczak Pawel J. Sikorski Joanna Zuberek Joanna Kowalska Jacek Jemielity Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation
description	Dinucleotide analogs of the messenger RNA cap (m<sup>7</sup>GpppN) are useful research tools and have potential applications as translational inhibitors or reagents for modification of in vitro transcribed mRNAs. It has been previously reported that replacing the methyl group at the N7-position with benzyl (Bn) produces a dinucleotide cap with superior properties. Here, we followed up on this finding by synthesizing 17 novel Bn<sup>7</sup>GpppG analogs and determining their structure–activity relationship regarding translation and translational inhibition. The compounds were prepared in two steps, including selective N7-alkylation of guanosine 5′-monophosphate by arylmethyl bromide followed by coupling with imidazole-activated GDP, with total yields varying from 22% to 62%. The compounds were then evaluated by determining their affinity for eukaryotic translation initiation factor 4E (eIF4E), testing their susceptibility to decapping pyrophosphatase, DcpS—which is most likely the major cellular enzyme targeting this type of compound—and determining their translation inhibitory properties in vitro. We also synthesized mRNAs capped with the evaluated compounds and tested their translational properties in A549 cells. Our studies identified N7-(4-halogenbenzyl) substituents as promising modifications in the contexts of either mRNA translation or translational inhibition. Finally, to gain more insight into the consequences at the molecular level of N7-benzylation of the mRNA cap, we determined the crystal structures of three compounds with eIF4E.
format	article
author	Radoslaw Wojcik Marek R. Baranowski Lukasz Markiewicz Dorota Kubacka Marcelina Bednarczyk Natalia Baran Anna Wojtczak Pawel J. Sikorski Joanna Zuberek Joanna Kowalska Jacek Jemielity
author_facet	Radoslaw Wojcik Marek R. Baranowski Lukasz Markiewicz Dorota Kubacka Marcelina Bednarczyk Natalia Baran Anna Wojtczak Pawel J. Sikorski Joanna Zuberek Joanna Kowalska Jacek Jemielity
author_sort	Radoslaw Wojcik
title	Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation
title_short	Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation
title_full	Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation
title_fullStr	Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation
title_full_unstemmed	Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation
title_sort	novel n7-arylmethyl substituted dinucleotide mrna 5′ cap analogs: synthesis and evaluation as modulators of translation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/31081b992c5141aa820199bd8e43fc38
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Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation

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