التفاصيل البيبلوغرافية
| العنوان: |
Structure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 N7-methyltransferases |
| المؤلفون: |
Hausdorff, M., Delpal, A., Barelier, S., Nicollet, L., Canard, B., Touret, F., /Colmant, Agathe, Coutard, B., Vasseur, J. J., Decroly, E., Debart, F. |
| سنة النشر: |
2023 |
| المجموعة: |
IRD (Institute de recherche pour le développement): Horizon |
| مصطلحات موضوعية: |
7-deaza-adenine, Arylsulfonamide, Bisubstrate, SARS-CoV-2, RNA cap, Methyltransferase, Structure -guided design |
| الوصف: |
The COVID-19 pandemic reveals the urgent need to develop new therapeutics targeting the SARS-CoV-2 replication machinery. The first antiviral drugs were nucleoside analogues targeting RdRp and protease inhibitors active on nsp5 Mpro. In addition to these common antiviral targets, SARS-CoV-2 codes for the highly conserved protein nsp14 harbouring N7-methyltransferase (MTase) activity. Nsp14 is involved in cap N7-methylation of viral RNA and its inhibition impairs viral RNA translation and immune evasion, making it an attractive new antiviral target. In this work, we followed a structure-guided drug design approach to design bisubstrates mimicking the S-adenosylmethionine methyl donor and RNA cap. We developed adenosine mimetics with an Narylsulfonamide moiety in the 5 '-position, recently described as a guanine mimicking the cap structure in a potent adenosine-derived nsp14 inhibitor. Here, the adenine moiety was replaced by hypoxanthine, N6-methyladenine, or C7-substituted 7-deaza-adenine. 26 novel adenosine mimetics were synthesized, one of which selectively inhibits nsp14 N7-MTase activity with a subnanomolar IC50 (and seven with a single-digit nanomolar IC50). In the most potent inhibitors, adenine was replaced by two different 7-deaza-adenines bearing either a phenyl or a 3-quinoline group at the C7-position via an ethynyl linker. These more complex compounds are barely active on the cognate human N7-MTase and docking experiments reveal that their selectivity of inhibition might result from the positioning of their C7 substitution in a SAM entry tunnel present in the nsp14 structure and absent in the hN7-MTase. These compounds show moderate antiviral activity against SARS-CoV-2 replication in cell culture, suggesting delivery or stability issue. |
| نوع الوثيقة: |
text |
| اللغة: |
English |
| Relation: |
https://www.documentation.ird.fr/hor/fdi:010088101; oai:ird.fr:fdi:010088101; Hausdorff M., Delpal A., Barelier S., Nicollet L., Canard B., Touret F., Colmant Agathe, Coutard B., Vasseur J. J., Decroly E., Debart F. Structure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 N7-methyltransferases. 2023, 256, p. 115474 [19 p.] |
| الاتاحة: |
https://www.documentation.ird.fr/hor/fdi:010088101 |
| رقم الانضمام: |
edsbas.580F3A1C |
| قاعدة البيانات: |
BASE |