2. Academic Validation
  3. System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2

System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2

  • Eur J Med Chem. 2021 Nov 15:224:113683. doi: 10.1016/j.ejmech.2021.113683.
Ilaria Vicenti 1,  Maria Grazia Martina 2,  Adele Boccuto 1,  Marta De Angelis 3,  Giorgia Giavarini 2,  Filippo Dragoni 1,  Serena Marchi 4,  Claudia Maria Trombetta 4,  Emmanuele Crespan 5,  Giovanni Maga 5,  Cecilia Eydoux 6,  Etienne Decroly 6,  Emanuele Montomoli 7,  Lucia Nencioni 3,  Maurizio Zazzi 1,  Marco Radi 8
Affiliations

Affiliations

  • 1 Department of Medical Biotechnologies, University of Siena, Siena, Italy.
  • 2 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124, Parma, Italy.
  • 3 Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
  • 4 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
  • 5 Istituto di Genetica Molecolare, IGM-CNR "Luigi Luca Cavalli-Sforza", Via Abbiategrasso 207, 27100, Pavia, Italy.
  • 6 AFMB, CNRS, Université Aix-Marseille, UMR 7257, Marseille, France.
  • 7 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; VisMederi s.r.l, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
  • 8 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124, Parma, Italy. Electronic address: marco.radi@unipr.it.
PMID: 34273661 DOI: 10.1016/j.ejmech.2021.113683
Abstract

The worldwide circulation of different viruses coupled with the increased frequency and diversity of new outbreaks, strongly highlight the need for new Antiviral drugs to quickly react against potential pandemic pathogens. Broad-spectrum Antiviral agents (BSAAs) represent the ideal option for a prompt response against multiple viruses, new and re-emerging. Starting from previously identified anti-flavivirus hits, we report herein the identification of promising BSAAs by submitting the multi-target 2,6-diaminopurine chemotype to a system-oriented optimization based on phenotypic screening on cell cultures infected with different viruses. Among the synthesized compounds, 6i showed low micromolar potency against Dengue, Zika, West Nile and Influenza A viruses (IC50 = 0.5-5.3 μM) with high selectivity index. Interestingly, 6i also inhibited SARS-CoV-2 replication in different cell lines, with higher potency on Calu-3 cells that better mimic the SARS-CoV-2 Infection in vivo (IC50 = 0.5 μM, SI = 240). The multi-target effect of 6i on Flavivirus replication was also analyzed in whole cell studies (in vitro selection and immunofluorescence) and against isolated host/viral targets.

Keywords

Broad-spectrum antivirals; Dengue; Diaminopurine; Influenza; SARS-CoV-2; West nile virus; Zika.

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