Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN

Khouloud Chakroun; Marwa Taouai; Vanessa Porkolab; Joanna Luczkowiak; Roman Sommer; Coraline Cheneau; David Mathiron; Mohamed Amine Ben Maaouia; Serge Pilard; Rym Abidi; Catherine Mullié; Franck Fieschi; Peter J. Cragg; Franck Halary; Rafael Delgado; Mohammed Benazza

doi:10.1021/acs.jmedchem.1c00818

Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN

Khouloud Chakroun, Marwa Taouai, Vanessa Porkolab, Joanna Luczkowiak, Roman Sommer, Coraline Cheneau, David Mathiron, Mohamed Amine Ben Maaouia, Serge Pilard, Rym Abidi, Catherine Mullié, Franck Fieschi, Peter J. Cragg, Franck Halary, Rafael Delgado, Mohammed Benazza

School of Applied Sciences

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

Abstract

In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.

Original language	English
Pages (from-to)	14332-14343
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	19
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00818
Publication status	Published - 15 Sep 2021

Bibliographical note

Funding Information:
Support from the “Conseil Régional de Picardie” and the LG2A-UMR7378-CNRS research group is gratefully acknowledged. K.C. and M.T. were financially supported by the Tunisian government. This work used the platforms of the Grenoble Instruction Centre (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL), notably SPR and MP3 platforms, with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX- 49-01) within the Grenoble Partnership for Structural Biology (PSB). V.P. was supported by la Région Rhône-Alpes. Research in RD lab is supported by grants from the Instituto de Investigación Carlos III (FIS PI 1801007) by the European Union Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868 and by Fundación Caixa-Health Research (Project StopEbola). The authors are grateful to the Chemical Biology of Carbohydrates, Helmholtz, Institute for Pharmaceutical Research Saarland, 66123 Saarbrücken, Germany, for the LecB inhibition assays. The authors thank the “Développement et Transfert à la Clinique platform ( http://www.cicnantes.fr/fr/component/glossary/Glossaire-1/C/CIC-35/ , CIC Biothérapies CBT 0503, CHU Nantes, France)” for providing elutriated monocytes, clinical-grade cytokines, and human serum albumin. The ARMINA Consortium (no. 201209680) supported Coraline Chéneau’s salary.

Publisher Copyright:
©

Keywords

Drug Discovery
Molecular Medicine

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Chakroun, K., Taouai, M., Porkolab, V., Luczkowiak, J., Sommer, R., Cheneau, C., Mathiron, D., Ben Maaouia, M. A., Pilard, S., Abidi, R., Mullié, C., Fieschi, F., Cragg, P. J., Halary, F., Delgado, R., & Benazza, M. (2021). Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN. Journal of Medicinal Chemistry, 64(19), 14332-14343. https://doi.org/10.1021/acs.jmedchem.1c00818

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title = "Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN",

abstract = "In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.",

keywords = "Drug Discovery, Molecular Medicine",

author = "Khouloud Chakroun and Marwa Taouai and Vanessa Porkolab and Joanna Luczkowiak and Roman Sommer and Coraline Cheneau and David Mathiron and {Ben Maaouia}, {Mohamed Amine} and Serge Pilard and Rym Abidi and Catherine Mulli{\'e} and Franck Fieschi and Cragg, {Peter J.} and Franck Halary and Rafael Delgado and Mohammed Benazza",

note = "Funding Information: Support from the “Conseil R{\'e}gional de Picardie” and the LG2A-UMR7378-CNRS research group is gratefully acknowledged. K.C. and M.T. were financially supported by the Tunisian government. This work used the platforms of the Grenoble Instruction Centre (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL), notably SPR and MP3 platforms, with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX- 49-01) within the Grenoble Partnership for Structural Biology (PSB). V.P. was supported by la R{\'e}gion Rh{\^o}ne-Alpes. Research in RD lab is supported by grants from the Instituto de Investigaci{\'o}n Carlos III (FIS PI 1801007) by the European Union Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868 and by Fundaci{\'o}n Caixa-Health Research (Project StopEbola). The authors are grateful to the Chemical Biology of Carbohydrates, Helmholtz, Institute for Pharmaceutical Research Saarland, 66123 Saarbr{\"u}cken, Germany, for the LecB inhibition assays. The authors thank the “D{\'e}veloppement et Transfert {\`a} la Clinique platform ( http://www.cicnantes.fr/fr/component/glossary/Glossaire-1/C/CIC-35/ , CIC Bioth{\'e}rapies CBT 0503, CHU Nantes, France)” for providing elutriated monocytes, clinical-grade cytokines, and human serum albumin. The ARMINA Consortium (no. 201209680) supported Coraline Ch{\'e}neau{\textquoteright}s salary. Publisher Copyright: {\textcopyright}",

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month = sep,

day = "15",

doi = "10.1021/acs.jmedchem.1c00818",

language = "English",

volume = "64",

pages = "14332--14343",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

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Chakroun, K, Taouai, M, Porkolab, V, Luczkowiak, J, Sommer, R, Cheneau, C, Mathiron, D, Ben Maaouia, MA, Pilard, S, Abidi, R, Mullié, C, Fieschi, F, Cragg, PJ, Halary, F, Delgado, R & Benazza, M 2021, 'Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN', Journal of Medicinal Chemistry, vol. 64, no. 19, pp. 14332-14343. https://doi.org/10.1021/acs.jmedchem.1c00818

Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN. / Chakroun, Khouloud; Taouai, Marwa; Porkolab, Vanessa et al.

In: Journal of Medicinal Chemistry, Vol. 64, No. 19, 15.09.2021, p. 14332-14343.

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

TY - JOUR

T1 - Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN

AU - Chakroun, Khouloud

AU - Taouai, Marwa

AU - Porkolab, Vanessa

AU - Luczkowiak, Joanna

AU - Sommer, Roman

AU - Cheneau, Coraline

AU - Mathiron, David

AU - Ben Maaouia, Mohamed Amine

AU - Pilard, Serge

AU - Abidi, Rym

AU - Mullié, Catherine

AU - Fieschi, Franck

AU - Cragg, Peter J.

AU - Halary, Franck

AU - Delgado, Rafael

AU - Benazza, Mohammed

N1 - Funding Information: Support from the “Conseil Régional de Picardie” and the LG2A-UMR7378-CNRS research group is gratefully acknowledged. K.C. and M.T. were financially supported by the Tunisian government. This work used the platforms of the Grenoble Instruction Centre (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL), notably SPR and MP3 platforms, with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX- 49-01) within the Grenoble Partnership for Structural Biology (PSB). V.P. was supported by la Région Rhône-Alpes. Research in RD lab is supported by grants from the Instituto de Investigación Carlos III (FIS PI 1801007) by the European Union Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868 and by Fundación Caixa-Health Research (Project StopEbola). The authors are grateful to the Chemical Biology of Carbohydrates, Helmholtz, Institute for Pharmaceutical Research Saarland, 66123 Saarbrücken, Germany, for the LecB inhibition assays. The authors thank the “Développement et Transfert à la Clinique platform ( http://www.cicnantes.fr/fr/component/glossary/Glossaire-1/C/CIC-35/ , CIC Biothérapies CBT 0503, CHU Nantes, France)” for providing elutriated monocytes, clinical-grade cytokines, and human serum albumin. The ARMINA Consortium (no. 201209680) supported Coraline Chéneau’s salary. Publisher Copyright: ©

PY - 2021/9/15

Y1 - 2021/9/15

N2 - In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.

AB - In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.

KW - Drug Discovery

KW - Molecular Medicine

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U2 - 10.1021/acs.jmedchem.1c00818

DO - 10.1021/acs.jmedchem.1c00818

M3 - Article

VL - 64

SP - 14332

EP - 14343

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 19

ER -

Chakroun K, Taouai M, Porkolab V, Luczkowiak J, Sommer R, Cheneau C et al. Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN. Journal of Medicinal Chemistry. 2021 Sep 15;64(19):14332-14343. https://doi.org/10.1021/acs.jmedchem.1c00818

Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN

Abstract

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