Structure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 N7-methyltransferases

• Published in: European journal of medicinal chemistry 2023-08, Vol.256, p.115474-115474, Article 115474
• Main Authors: Hausdorff, Marcel, Delpal, Adrien, Barelier, Sarah, Nicollet, Laura, Canard, Bruno, Touret, Franck, Colmant, Agathe, Coutard, Bruno, Vasseur, Jean-Jacques, Decroly, Etienne, Debart, Françoise
• Format: Article
• Language: English
• Subjects: 7-deaza-adenine; Adenine; Adenosine - pharmacology; Antiviral Agents - pharmacology; Arylsulfonamide; Bisubstrate; Chemical Sciences; COVID-19; Humans; Medicinal Chemistry; Methyltransferases - metabolism; Pandemics; Research Paper; RNA cap Methyltransferase; RNA, Viral - genetics; S-Adenosylmethionine; SARS-CoV-2; SARS-CoV-2 - genetics; Structure-guided design; Viral Nonstructural Proteins - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115474

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 N-arylsulfonamide 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. [Display omitted] •Adenosine mimetics as bisubstrates of coronavirus N7-methyltransferase nsp14.•Nucleosides with 5′-N-arylsulfonamide moieties combined with hypoxanthine, N6-methyladenine, C7-substituted 7-deaza-adenine.•One subnanomolar and selective inhibitor of SARS-CoVs nsp14 N7-methyltransferase.•Selective pan-CoV inhibitors with low activity on hRNMT and no activity on DV3 NS5.•Molecular docking studies support observed SAR.