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<p>SARS-CoV-2 still poses as a threat to health systems despite the vaccination and the use of emergency repurposed drugs. Therefore, the development of novel anti-SARS-CoV-2 compounds is still needed. Organometallic copper(I)-N-heterocyclic carbenes [Cu(NHC)] are a class of metallodrugs that hold promise for drug development due to their variety of geometries, charges, and ligand design. Here we evaluated the activity of Cu(IPr)Cl, Cu(IMes)Cl, and [Cu(IMes)<sub>2</sub>]BF<sub>4</sub> molecules against SARS-CoV-2 infection. Through a dose–response assay using A549-AT cells and the SARS-CoV-2-Wuhan infectious clone expressing mNeonGreen (SARS-CoV-2-mNeonGreen), Cu(IPr)Cl, Cu(IMes)Cl, and [Cu(IMes)<sub>2</sub>]BF<sub>4</sub> inhibited SARS-CoV-2 replication with a selectivity index (SI) of 11.23, 10.84, and 5.94, respectively. The complexes Cu(IMes)Cl and [Cu(IMes)<sub>2</sub>]BF<sub>4</sub> inhibited all stages of viral replication (pretreatment: 99.9% and 87.7%, entry: 99.6% and 74%, post-entry steps: 99.6% and 87.6%, respectively), while Cu(IPr)Cl impaired only entry (48%) and post-entry steps (95%). In addition, Cu(IMes)Cl and [Cu(IMes)<sub>2</sub>]BF<sub>4</sub> complexes decreased the titres of both Delta and Omicron variants, while Cu(IPr)Cl only inhibited Omicron. In addition, [Cu(IMes)<sub>2</sub>]BF<sub>4</sub> was able to decrease cell to cell spread of SARS-CoV-2; and for Cu(IMes)Cl a strong interaction with PL<sup>pro</sup> was revealed. Based on this data further investigations of Cu(I) based organometallics are warranted and Cu(IPr)Cl and Cu(IMes)Cl may be considered for utilization in pre-clinical assays.</p> Graphical Abstract <p></p>

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Cu(I)-N-Heterocyclic carbenes as potent inhibitors of SARS-CoV-2 replication

  • 期刊论文

  • 发表日期：

    2025年12月7日

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  • Igor Andrade Santos,
  • Josielle V. Fontes,
  • Gustavo C. Rodrigues,
  • Mariana Ortiz de Godoy,
  • Glaucius Oliva,
  • Rafael V. C. Guido,
  • Andres Merits,
  • Camilla Abbehausen,
  • Mark Harris,
  • Ana Carolina Gomes Jardim

摘要

SARS-CoV-2 still poses as a threat to health systems despite the vaccination and the use of emergency repurposed drugs. Therefore, the development of novel anti-SARS-CoV-2 compounds is still needed. Organometallic copper(I)-N-heterocyclic carbenes [Cu(NHC)] are a class of metallodrugs that hold promise for drug development due to their variety of geometries, charges, and ligand design. Here we evaluated the activity of Cu(IPr)Cl, Cu(IMes)Cl, and [Cu(IMes)2]BF4 molecules against SARS-CoV-2 infection. Through a dose–response assay using A549-AT cells and the SARS-CoV-2-Wuhan infectious clone expressing mNeonGreen (SARS-CoV-2-mNeonGreen), Cu(IPr)Cl, Cu(IMes)Cl, and [Cu(IMes)2]BF4 inhibited SARS-CoV-2 replication with a selectivity index (SI) of 11.23, 10.84, and 5.94, respectively. The complexes Cu(IMes)Cl and [Cu(IMes)2]BF4 inhibited all stages of viral replication (pretreatment: 99.9% and 87.7%, entry: 99.6% and 74%, post-entry steps: 99.6% and 87.6%, respectively), while Cu(IPr)Cl impaired only entry (48%) and post-entry steps (95%). In addition, Cu(IMes)Cl and [Cu(IMes)2]BF4 complexes decreased the titres of both Delta and Omicron variants, while Cu(IPr)Cl only inhibited Omicron. In addition, [Cu(IMes)2]BF4 was able to decrease cell to cell spread of SARS-CoV-2; and for Cu(IMes)Cl a strong interaction with PLpro was revealed. Based on this data further investigations of Cu(I) based organometallics are warranted and Cu(IPr)Cl and Cu(IMes)Cl may be considered for utilization in pre-clinical assays.

Graphical Abstract