1. System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2
- Author
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Adele Boccuto, Ilaria Vicenti, Giovanni Maga, Maurizio Zazzi, Marco Radi, Claudia Maria Trombetta, Serena Marchi, Maria Grazia Martina, Emmanuele Crespan, Lucia Nencioni, Emanuele Montomoli, Etienne Decroly, Filippo Dragoni, Marta De Angelis, Cécilia Eydoux, Giorgia Giavarini, Università degli Studi di Siena = University of Siena (UNISI), University of Parma = Università degli studi di Parma [Parme, Italie], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Istituto di Genetica Molecolare (IGM), Consiglio Nazionale delle Ricerche (CNR), Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli studi di Parma = University of Parma (UNIPR), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), and Aix Marseille Université (AMU)
- Subjects
Diaminopurine ,Phenotypic screening ,viruses ,[SDV]Life Sciences [q-bio] ,Broad-spectrum antivirals ,Dengue ,Influenza ,SARS-CoV-2 ,West nile virus ,Zika ,Immunofluorescence ,Virus Replication ,Antiviral Agents ,Virus ,Article ,Dengue fever ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Pandemic ,medicine ,[CHIM]Chemical Sciences ,Potency ,Molecular Targeted Therapy ,diaminopurine ,broad-spectrum antivirals ,dengue ,zika ,west nile virus ,influenza ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Pharmacology ,0303 health sciences ,medicine.diagnostic_test ,biology ,Chemistry ,Flavivirus ,Organic Chemistry ,General Medicine ,medicine.disease ,biology.organism_classification ,Orthomyxoviridae ,Virology ,3. Good health ,Cell culture ,Purines ,030220 oncology & carcinogenesis ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie - 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., Graphical abstract Image 1
- Published
- 2021
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