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

doi:10.1002/cmdc.202100483

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

University of Parma
University of Siena
Institute of Legal Informatics and Judicial Systems (IGSiG-CNR)
University of Genoa
Utrecht University

Research output: Contribution to journal › Article › Academic › peer-review

29 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 language	English
Pages (from-to)	3548-3552
Number of pages	5
Journal	ChemMedChem
Volume	16
Issue number	23
Early online date	11 Aug 2021
DOIs	https://doi.org/10.1002/cmdc.202100483
Publication status	Published - 6 Dec 2021
Externally published	Yes

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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Bithiazole Inhibitors of Phosphatidylinositol 4-Kinase (PI4KIIIβ) as Broad-Spectrum Antivirals Blocking the Replication of SARS-CoV-2, Zika Virus, and Human RhinovirusesFinal published version, 1.28 MBLicence: CC BY

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Grazia Martina, M., Vicenti, I., Bauer, L., Crespan, E., Rango, E., Boccuto, A., Olivieri, N., Incerti, M., Zwaagstra, M., Allodi, M., Bertoni, S., Dreassi, E., Zazzi, M., van Kuppeveld, F. J. M., Maga, G., & Radi, M. (2021). Bithiazole Inhibitors of Phosphatidylinositol 4-Kinase (PI4KIIIβ) as Broad-Spectrum Antivirals Blocking the Replication of SARS-CoV-2, Zika Virus, and Human Rhinoviruses. ChemMedChem, 16(23), 3548-3552. https://doi.org/10.1002/cmdc.202100483

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

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.",

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

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′Universit{\`a} 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{\l}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. Publisher Copyright: {\textcopyright} 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.",

year = "2021",

month = dec,

day = "6",

doi = "10.1002/cmdc.202100483",

language = "English",

volume = "16",

pages = "3548--3552",

journal = "ChemMedChem",

issn = "1860-7179",

publisher = "John Wiley \& Sons Ltd.",

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}

Grazia Martina, M, Vicenti, I, Bauer, L, Crespan, E, Rango, E, Boccuto, A, Olivieri, N, Incerti, M, Zwaagstra, M, Allodi, M, Bertoni, S, Dreassi, E, Zazzi, M, van Kuppeveld, FJM, Maga, G & Radi, M 2021, 'Bithiazole Inhibitors of Phosphatidylinositol 4-Kinase (PI4KIIIβ) as Broad-Spectrum Antivirals Blocking the Replication of SARS-CoV-2, Zika Virus, and Human Rhinoviruses', ChemMedChem, vol. 16, no. 23, pp. 3548-3552. https://doi.org/10.1002/cmdc.202100483

Bithiazole Inhibitors of Phosphatidylinositol 4-Kinase (PI4KIIIβ) as Broad-Spectrum Antivirals Blocking the Replication of SARS-CoV-2, Zika Virus, and Human Rhinoviruses. / Grazia Martina, Maria; Vicenti, Ilaria; Bauer, Lisa et al.
In: ChemMedChem, Vol. 16, No. 23, 06.12.2021, p. 3548-3552.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Bithiazole Inhibitors of Phosphatidylinositol 4-Kinase (PI4KIIIβ) as Broad-Spectrum Antivirals Blocking the Replication of SARS-CoV-2, Zika Virus, and Human Rhinoviruses

AU - Grazia Martina, Maria

AU - Vicenti, Ilaria

AU - Bauer, Lisa

AU - Crespan, Emmanuele

AU - Rango, Enrico

AU - Boccuto, Adele

AU - Olivieri, Noemi

AU - Incerti, Matteo

AU - Zwaagstra, Marleen

AU - Allodi, Marika

AU - Bertoni, Simona

AU - Dreassi, Elena

AU - Zazzi, Maurizio

AU - van Kuppeveld, Frank J.M.

AU - Maga, Giovanni

AU - Radi, Marco

N1 - 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.

PY - 2021/12/6

Y1 - 2021/12/6

N2 - 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.

AB - 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.

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DO - 10.1002/cmdc.202100483

M3 - Article

C2 - 34382337

AN - SCOPUS:85114337173

SN - 1860-7179

VL - 16

SP - 3548

EP - 3552

JO - ChemMedChem

JF - ChemMedChem

IS - 23

ER -

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

Abstract

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