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Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one...

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Autores principales: Elste, James, Kaltenbach, Dominik, Patel, Vraj R., Nguyen, Max T., Sharthiya, Harsh, Tandon, Ritesh, Mehta, Satish K., Volin, Michael V., Fornaro, Michele, Tiwari, Vaibhav, Desai, Umesh R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084493/
https://www.ncbi.nlm.nih.gov/pubmed/32121406
http://dx.doi.org/10.3390/ijms21051676
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author Elste, James
Kaltenbach, Dominik
Patel, Vraj R.
Nguyen, Max T.
Sharthiya, Harsh
Tandon, Ritesh
Mehta, Satish K.
Volin, Michael V.
Fornaro, Michele
Tiwari, Vaibhav
Desai, Umesh R.
author_facet Elste, James
Kaltenbach, Dominik
Patel, Vraj R.
Nguyen, Max T.
Sharthiya, Harsh
Tandon, Ritesh
Mehta, Satish K.
Volin, Michael V.
Fornaro, Michele
Tiwari, Vaibhav
Desai, Umesh R.
author_sort Elste, James
collection PubMed
description Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a ‘poly-pharmacy’ approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV.
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spelling pubmed-70844932020-03-24 Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule Elste, James Kaltenbach, Dominik Patel, Vraj R. Nguyen, Max T. Sharthiya, Harsh Tandon, Ritesh Mehta, Satish K. Volin, Michael V. Fornaro, Michele Tiwari, Vaibhav Desai, Umesh R. Int J Mol Sci Article Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a ‘poly-pharmacy’ approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV. MDPI 2020-02-29 /pmc/articles/PMC7084493/ /pubmed/32121406 http://dx.doi.org/10.3390/ijms21051676 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Elste, James
Kaltenbach, Dominik
Patel, Vraj R.
Nguyen, Max T.
Sharthiya, Harsh
Tandon, Ritesh
Mehta, Satish K.
Volin, Michael V.
Fornaro, Michele
Tiwari, Vaibhav
Desai, Umesh R.
Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule
title Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule
title_full Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule
title_fullStr Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule
title_full_unstemmed Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule
title_short Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule
title_sort inhibition of human cytomegalovirus entry into host cells through a pleiotropic small molecule
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084493/
https://www.ncbi.nlm.nih.gov/pubmed/32121406
http://dx.doi.org/10.3390/ijms21051676
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