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1.
Angew Chem Int Ed Engl ; 61(46): e202205858, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-36115062

RESUMO

SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome.


Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Humanos , Proteoma , Ligantes , Desenho de Fármacos
2.
Angew Chem Int Ed Engl ; 60(35): 19191-19200, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34161644

RESUMO

SARS-CoV-2 contains a positive single-stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 RNA elements were identified as conserved between SARS-CoV and SARS-CoV-2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these elements fold independently, in line with data from in vivo and ex-vivo structural probing experiments. These elements contain non-base-paired regions that potentially harbor ligand-binding pockets. Here, we performed an NMR-based screening of a poised fragment library of 768 compounds for binding to these RNAs, employing three different 1 H-based 1D NMR binding assays. The screening identified common as well as RNA-element specific hits. The results allow selection of the most promising of the 15 RNA elements as putative drug targets. Based on the identified hits, we derive key functional units and groups in ligands for effective targeting of the RNA of SARS-CoV-2.


Assuntos
Genoma , RNA Viral/metabolismo , SARS-CoV-2/genética , Bibliotecas de Moléculas Pequenas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ligantes , Estrutura Molecular , Conformação de Ácido Nucleico , Espectroscopia de Prótons por Ressonância Magnética , RNA Viral/química , Bibliotecas de Moléculas Pequenas/química
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