2. Academic Validation
  3. Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71

Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71

  • Eur J Med Chem. 2022 Nov 24;246:114942. doi: 10.1016/j.ejmech.2022.114942.
Martina Salerno 1,  Carmine Varricchio 2,  Federica Bevilacqua 2,  Dirk Jochmans 3,  Johan Neyts 3,  Andrea Brancale 2,  Salvatore Ferla 4,  Marcella Bassetto 5
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Science and Engineering, Swansea University, Swansea, SA2 8PP, UK.
  • 2 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK.
  • 3 KU Leuven - Rega Institute, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium.
  • 4 Medical School, Faculty of Medicine, Health and Life Science, Swansea University, Swansea, SA2 8PP, UK.
  • 5 Department of Chemistry, College of Science and Engineering, Swansea University, Swansea, SA2 8PP, UK. Electronic address: marcella.bassetto@swansea.ac.uk.
PMID: 36455356 DOI: 10.1016/j.ejmech.2022.114942
Abstract

Different viruses belonging to distinct viral families, such as Enterovirus 71, rely on the host methyltransferase METTL3 for the completion of fundamental cytoplasmic stages of their life cycle. Modulation of the activity of this Enzyme could therefore provide a broad-spectrum approach to interfere with viral infections caused by viruses that depend on its activity for the completion of their viral cycle. With the aim to identify Antiviral therapeutics with this effect, a series of new nucleoside analogues was rationally designed to act as inhibitors of human METTL3, as a novel approach to interfere with a range of viral infections. Guided by molecular docking studies on the SAM binding pocket of the Enzyme, 24 compounds were prepared following multiple-step synthetic protocols, and evaluated for their ability to interfere with the replication of different viruses in cell-based systems, and to directly inhibit the activity of METTL3. While different molecules displayed moderate inhibition of the human methyltransferase in vitro, multiple novel, potent and selective inhibitors of Enterovirus 71 were identified.

Keywords

EV71; METTL3; Molecular modelling; Novel small-molecule antiviral agents; Prodrugs; Synthetic organic chemistry.

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