Copper(II) benzyloxychalcone analogues as new potential metallodrugs against SARS-CoV-2 replication

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Abstract
Chalcones, a naturally occurring class of molecules found in various plants, serve as both precursors and final products in the biosynthesis of flavonoids. Renowned for their diverse therapeutic actions, chalcones demonstrate anti-inflammatory, antitumoral, antimalarial and antiviral activities. The structure of chalcones allows chemical manipulation, making them attractive for metal coordination, such as with copper, an essential metal for living organisms. Here, we characterize the activity of CuL 2 phen and CuL 1 phen against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in which L1 and L2 are two forms of the chalcones 3-(4-(benzyloxy)phenyl)-1-(4-fluoro-2-hydroxyphenyl)prop-2-en-1-one and 3-(4-(benzyloxy)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one, respectively, and phen is phenanthroline. CuL 1 phen and CuL 2 phen anti-SARS-CoV-2 activity were studied in the viral replication cycle employing both the SARS-CoV-2-NeonGreen infectious clone and wild-type isolates. The SI of CuL 1 phen and CuL 2 phen was found to be 1.7 and 5.5, respectively, demonstrating that CuL 2 phen is a more promising compound. CuL 2 phen impaired SARS-CoV-2 entry, predicted by molecular docking calculations to disrupt the glycoprotein S and angiotensin-converting enzyme 2 (ACE2) binding, emphasized by the low EC 50 in pseudotyped virus entry assay. Further, CuL 2 phen was identified as SARS-CoV-2 post-entry inhibitor, probably due to its strong interaction with SARS-CoV-2 double stranded RNA. Altogether, the data suggest that CuL 2 phen acts by impairing SARS-CoV-2 entry by disrupting the viral envelope as well as interrupting RNA replication through specifically intercalating into the dsRNA. The obtained results give us mechanistic insights into the activity of this promising Cu(II) metallodrug candidate in SARS-CoV-2 infection.
Funding Information
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2020/04602-9)
  • Medical Research Scotland (MR/Y004205/1)
  • Medical Research Scotland (G2P2-UK)
  • Fundação de Amparo à Pesquisa do Estado de Minas Gerais (APQ-04686-22)
  • Fundação de Amparo à Pesquisa do Estado de Minas Gerais (APQ-01487-22)
  • Wellcome Trust (302268/Z/23/Z)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (404668/2021-6)
  • Wellcome Trust (221538/Z/20/Z)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (#88881.506794/2020-01)
  • Medical Research Foundation (MR/V036904/1)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2013/07600-3)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (310736/2022-6)
  • Biotechnology and Biological Sciences Research Council (BBS/E/I/00007038)
  • Medical Research Foundation (MR/S001026/1)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2022/02618-0)

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