Bithiazole Inhibitors of Phosphatidylinositol 4-Kinase (PI4KIIIβ) as Broad-Spectrum Antivirals Blocking the Replication of SARS-CoV-2, Zika Virus, and Human Rhinoviruses

Maria Grazia Martina, Ilaria Vicenti, Lisa Bauer, Emmanuele Crespan, Enrico Rango, Adele Boccuto, Noemi Olivieri, Matteo Incerti, Marleen Zwaagstra, Marika Allodi, Simona Bertoni, Elena Dreassi, Maurizio Zazzi, Frank J.M. van Kuppeveld, Giovanni Maga, Marco Radi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

Over half a century since the description of the first antiviral drug, “old” re-emerging viruses and “new” emerging viruses still represent a serious threat to global health. Their high mutation rate and rapid selection of resistance toward common antiviral drugs, together with the increasing number of co-infections, make the war against viruses quite challenging. Herein we report a host-targeted approach, based on the inhibition of the lipid kinase PI4KIIIβ, as a promising strategy for inhibiting the replication of multiple viruses hijacking this protein. We show that bithiazole inhibitors of PI4KIIIβ block the replication of human rhinoviruses (hRV), Zika virus (ZIKV) and SARS-CoV-2 at low micromolar and sub-micromolar concentrations. However, while the anti-hRV/ZIKV activity can be directly linked to PI4KIIIβ inhibition, the role of PI4KIIIβ in SARS-CoV-2 entry/replication is debated.

Original languageEnglish
Pages (from-to)3548-3552
Number of pages5
JournalChemMedChem
Volume16
Issue number23
Early online date11 Aug 2021
DOIs
Publication statusPublished - 6 Dec 2021
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Ministero dell?Istruzione, dell?Universit? della Ricerca Italiano (MIUR) (PRIN 2017 project N. 2017BMK8JR, ?ORIGINALE CHEMIAE in Antiviral Strategy ? Origin and Modernization of Multi-Component Chemistry as a Source of Innovative Broad Spectrum Antiviral Strategy? to M.R. and M.Z.). This work was also supported by a research grants from the European Union (Horizon 2020 Marie Sk?odowska-Curie ETN ?ANTIVIRALS?, grant agreement number 642434 to F.J.M.v.K.), by the Italian Cancer Research Association (MFAG2016 18811 and IG 2020 ID 24448 to E.C.; IG2017-20762 to G.M.) and by MIUR (PRIN 2017 project N. 2017SA5837 to G.M.). We thank Simona De Pasquale for excellent technical assistance. Open Access Funding provided by Universita degli Studi di Parma within the CRUI-CARE Agreement.

Funding Information:
This work was supported by the Ministero dell′Istruzione, dell′Università della Ricerca Italiano (MIUR) (PRIN 2017 project N. 2017BMK8JR, “ORIGINALE CHEMIAE in Antiviral Strategy – Origin and Modernization of Multi‐Component Chemistry as a Source of Innovative Broad Spectrum Antiviral Strategy” to M.R. and M.Z.). This work was also supported by a research grants from the European Union (Horizon 2020 Marie Skłodowska‐Curie ETN “ANTIVIRALS”, grant agreement number 642434 to F.J.M.v.K.), by the Italian Cancer Research Association (MFAG2016 18811 and IG 2020 ID 24448 to E.C.; IG2017‐20762 to G.M.) and by MIUR (PRIN 2017 project N. 2017SA5837 to G.M.). We thank Simona De Pasquale for excellent technical assistance. Open Access Funding provided by Universita degli Studi di Parma within the CRUI‐CARE Agreement.

Publisher Copyright:
© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.

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