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Article: Inhibitors of Venezuelan Equine Encephalitis Virus Identified Based on Host Interaction Partners of Viral Non-Structural Protein 3

Bakovic, Allison / Bhalla, Nishank / Alem, Farhang / Campbell, Catherine / Zhou, Weidong / Narayanan, Aarthi

Viruses. 2021 Aug. 03, v. 13, no. 8

2021

Abstract: Venezuelan equine encephalitis virus (VEEV) is a new world alphavirus and a category B select agent. Currently, no FDA-approved vaccines or therapeutics are available to treat VEEV exposure and resultant disease manifestations. The C-terminus of the VEEV ...

Abstract	Venezuelan equine encephalitis virus (VEEV) is a new world alphavirus and a category B select agent. Currently, no FDA-approved vaccines or therapeutics are available to treat VEEV exposure and resultant disease manifestations. The C-terminus of the VEEV non-structural protein 3 (nsP3) facilitates cell-specific and virus-specific host factor binding preferences among alphaviruses, thereby providing targets of interest when designing novel antiviral therapeutics. In this study, we utilized an overexpression construct encoding HA-tagged nsP3 to identify host proteins that interact with VEEV nsP3 by mass spectrometry. Bioinformatic analyses of the putative interactors identified 42 small molecules with the potential to inhibit the host interaction targets, and thus potentially inhibit VEEV. Three inhibitors, tomatidine, citalopram HBr, and Z-VEID-FMK, reduced replication of both the TC-83 strain and the Trinidad donkey (TrD) strain of VEEV by at least 10-fold in astrocytoma, astroglial, and microglial cells. Further, these inhibitors reduced replication of the related New World (NW) alphavirus Eastern equine encephalitis virus (EEEV) in multiple cell types, thus demonstrating broad-spectrum antiviral activity. Time-course assays revealed all three inhibitors reduced both infectious particle production and positive-sense RNA levels post-infection. Further evaluation of the putative host targets for the three inhibitors revealed an interaction of VEEV nsP3 with TFAP2A, but not eIF2S2. Mechanistic studies utilizing siRNA knockdowns demonstrated that eIF2S2, but not TFAP2A, supports both efficient TC-83 replication and genomic RNA synthesis, but not subgenomic RNA translation. Overall, this work reveals the composition of the VEEV nsP3 proteome and the potential to identify host-based, broad spectrum therapeutic approaches to treat new world alphavirus infections.
Keywords	Eastern equine encephalitis virus ; Venezuelan equine encephalitis virus ; antiviral properties ; asses ; astrocytoma ; bioinformatics ; genomics ; mass spectrometry ; proteome ; therapeutics ; viral nonstructural proteins ; Trinidad and Tobago
Language	English
Dates of publication	2021-0803
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13081533
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Inhibitors of Venezuelan Equine Encephalitis Virus Identified Based on Host Interaction Partners of Viral Non-Structural Protein 3.

Bakovic, Allison / Bhalla, Nishank / Alem, Farhang / Campbell, Catherine / Zhou, Weidong / Narayanan, Aarthi

Viruses

2021 Volume 13, Issue 8

Abstract	Venezuelan equine encephalitis virus (VEEV) is a new world alphavirus and a category B select agent. Currently, no FDA-approved vaccines or therapeutics are available to treat VEEV exposure and resultant disease manifestations. The C-terminus of the VEEV non-structural protein 3 (nsP3) facilitates cell-specific and virus-specific host factor binding preferences among alphaviruses, thereby providing targets of interest when designing novel antiviral therapeutics. In this study, we utilized an overexpression construct encoding HA-tagged nsP3 to identify host proteins that interact with VEEV nsP3 by mass spectrometry. Bioinformatic analyses of the putative interactors identified 42 small molecules with the potential to inhibit the host interaction targets, and thus potentially inhibit VEEV. Three inhibitors, tomatidine, citalopram HBr, and Z-VEID-FMK, reduced replication of both the TC-83 strain and the Trinidad donkey (TrD) strain of VEEV by at least 10-fold in astrocytoma, astroglial, and microglial cells. Further, these inhibitors reduced replication of the related New World (NW) alphavirus Eastern equine encephalitis virus (EEEV) in multiple cell types, thus demonstrating broad-spectrum antiviral activity. Time-course assays revealed all three inhibitors reduced both infectious particle production and positive-sense RNA levels post-infection. Further evaluation of the putative host targets for the three inhibitors revealed an interaction of VEEV nsP3 with TFAP2A, but not eIF2S2. Mechanistic studies utilizing siRNA knockdowns demonstrated that eIF2S2, but not TFAP2A, supports both efficient TC-83 replication and genomic RNA synthesis, but not subgenomic RNA translation. Overall, this work reveals the composition of the VEEV nsP3 proteome and the potential to identify host-based, broad spectrum therapeutic approaches to treat new world alphavirus infections.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Cell Line ; Chlorocebus aethiops ; Encephalitis Virus, Venezuelan Equine/drug effects ; Encephalitis Virus, Venezuelan Equine/genetics ; Horses ; Host Microbial Interactions/drug effects ; Humans ; Proteome ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/classification ; Viral Nonstructural Proteins/genetics ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Proteome ; Viral Nonstructural Proteins
Language	English
Publishing date	2021-08-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13081533
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture.

Bakovic, Allison / Risner, Kenneth / Bhalla, Nishank / Alem, Farhang / Chang, Theresa L / Weston, Warren K / Harness, Jane A / Narayanan, Aarthi

Viruses

2021 Volume 13, Issue 2

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than two million deaths worldwide since it was first detected in 2019. There is a critical global ... ...

Abstract	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than two million deaths worldwide since it was first detected in 2019. There is a critical global need for therapeutic intervention strategies that can be deployed to safely treat COVID-19 disease and reduce associated morbidity and mortality. Increasing evidence shows that both natural and synthetic antimicrobial peptides (AMPs), also referred to as Host Defense Proteins/Peptides (HDPs), can inhibit SARS-CoV-2, paving the way for the potential clinical use of these molecules as therapeutic options. In this manuscript, we describe the potent antiviral activity exerted by brilacidin-a de novo designed synthetic small molecule that captures the biological properties of HDPs-on SARS-CoV-2 in a human lung cell line (Calu-3) and a monkey cell line (Vero). These data suggest that SARS-CoV-2 inhibition in these cell culture models is likely to be a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 against different strains of the virus in cell culture.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Animals ; Antiviral Agents/pharmacology ; COVID-19/virology ; Cell Culture Techniques ; Cell Line ; Chlorocebus aethiops ; Defensins/pharmacology ; Guanidines/pharmacology ; Humans ; Peptidomimetics/pharmacology ; Pyrimidines/pharmacology ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Vero Cells ; Virus Internalization/drug effects ; Virus Replication/drug effects ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Defensins ; Guanidines ; Peptidomimetics ; Pyrimidines ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; brilacidin (I1679X069H) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2021-02-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13020271
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: New World alphavirus protein interactomes from a therapeutic perspective.

Carey, Brian D / Bakovic, Allison / Callahan, Victoria / Narayanan, Aarthi / Kehn-Hall, Kylene

Antiviral research

2019 Volume 163, Page(s) 125–139

Abstract: The New World alphaviruses, Venezuelan, eastern and western equine encephalitis viruses (VEEV, EEEV, and WEEV), are important human pathogens due to their ability to cause varying levels of morbidity and mortality in humans. There is also concern about ... ...

Abstract	The New World alphaviruses, Venezuelan, eastern and western equine encephalitis viruses (VEEV, EEEV, and WEEV), are important human pathogens due to their ability to cause varying levels of morbidity and mortality in humans. There is also concern about VEEV and EEEV being used as bioweapons. Currently, a FDA-approved antiviral is lacking for New World alphaviruses. In this review, the function of each viral protein is discussed with an emphasis on how these functions can be targeted by therapeutics. Both direct acting antivirals as well as inhibitors that impact host protein interactions with viral proteins are described. Non-structural protein 3 (nsP3), capsid, and E2 proteins have garnered attention in recent years, whereas little is known regarding host protein interactions of the other viral proteins and is an important avenue for future study.
MeSH term(s)	Alphavirus/drug effects ; Alphavirus/physiology ; Alphavirus Infections/drug therapy ; Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Cell Line ; Clinical Trials as Topic ; Host Microbial Interactions/drug effects ; Humans ; Mice ; Viral Proteins/chemistry ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Viral Proteins
Language	English
Publishing date	2019-01-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2019.01.015
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Maraviroc inhibits SARS-CoV-2 multiplication and s-protein mediated cell fusion in cell culture.

Risner, Kenneth H / Tieu, Katie V / Wang, Yafei / Getz, Michael / Bakovic, Allison / Bhalla, Nishank / Nathan, Steven D / Conway, Daniel E / Macklin, Paul / Narayanan, Aarthi / Alem, Farhang

bioRxiv : the preprint server for biology

2022

Abstract: In an effort to identify therapeutic intervention strategies for the treatment of COVID-19, we have investigated a selection of FDA-approved small molecules and biologics that are commonly used to treat other human diseases. A investigation into 18 small ...

Abstract	In an effort to identify therapeutic intervention strategies for the treatment of COVID-19, we have investigated a selection of FDA-approved small molecules and biologics that are commonly used to treat other human diseases. A investigation into 18 small molecules and 3 biologics was conducted in cell culture and the impact of treatment on viral titer was quantified by plaque assay. The investigation identified 4 FDA-approved small molecules, Maraviroc, FTY720 (Fingolimod), Atorvastatin and Nitazoxanide that were able to inhibit SARS-CoV-2 infection. Confocal microscopy with over expressed S-protein demonstrated that Maraviroc reduced the extent of S-protein mediated cell fusion as observed by fewer multinucleate cells in the context of drug-treatment. Mathematical modeling of drug-dependent viral multiplication dynamics revealed that prolonged drug treatment will exert an exponential decrease in viral load in a multicellular/tissue environment. Taken together, the data demonstrate that Maraviroc, Fingolimod, Atorvastatin and Nitazoxanide inhibit SARS-CoV-2 in cell culture.
Keywords	covid19
Language	English
Publishing date	2022-11-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.08.12.246389
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Efficacy of FDA-Approved Anti-Inflammatory Drugs Against Venezuelan Equine Encephalitis Virus Infection.

Risner, Kenneth / Ahmed, Aslaa / Bakovic, Allison / Kortchak, Stephanie / Bhalla, Nishank / Narayanan, Aarthi

Viruses

2019 Volume 11, Issue 12

Abstract: Venezuelan equine encephalitis virus (VEEV) is a category B select agent pathogen that can be aerosolized. Infections in murine models and humans can advance to an encephalitic phenotype which may result in long-term neurological complications or death. ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV) is a category B select agent pathogen that can be aerosolized. Infections in murine models and humans can advance to an encephalitic phenotype which may result in long-term neurological complications or death. No specific FDA-approved treatments or vaccines are available for the treatment or prevention of VEEV infection. Neurotropic viral infections have two damaging components: neuronal death caused by viral replication, and damage from the subsequent inflammatory response. Reducing the level of inflammation may lessen neurological tissue damage that often arises following VEEV infection. In this study, three commercially available anti-inflammatory drugs, Celecoxib, Rolipram, and Tofacitinib, were evaluated for antiviral activity in an astrocyte and a microglial model of VEEV infection. The inhibitors were tested against the vaccine strain VEEV TC-83, as well as the wild-type VEEV Trinidad donkey strain. Celecoxib, Tofacitinib, and Rolipram significantly decreased viral titers both after pre-treatment and post-treatment of infected cells. VEEV Trinidad Donkey (TrD) titers were reduced 6.45-fold in cells treated with 50 µM of Celecoxib, 2.45-fold when treated with 50 µM of Tofacitinib, and 1.81-fold when treated with 50 µM of Rolipram. Celecoxib was also shown to decrease inflammatory gene expression in the context of TC-83 infection. Overall, Celecoxib demonstrated potency as a countermeasure strategy that slowed VEEV infection and infection-induced inflammation in an in vitro model.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Antiviral Agents/pharmacology ; Astrocytes/drug effects ; Cell Line ; Cell Survival/drug effects ; Cytokines/metabolism ; Drug Approval ; Drug Repositioning ; Encephalitis Virus, Venezuelan Equine/drug effects ; Encephalomyelitis, Venezuelan Equine/drug therapy ; Encephalomyelitis, Venezuelan Equine/virology ; Humans ; Microglia/drug effects ; United States ; United States Food and Drug Administration ; Virus Replication/drug effects
Chemical Substances	Anti-Inflammatory Agents ; Antiviral Agents ; Cytokines
Language	English
Publishing date	2019-12-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v11121151
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Venezuelan Equine Encephalitis Virus nsP3 Phosphorylation Can Be Mediated by IKKβ Kinase Activity and Abrogation of Phosphorylation Inhibits Negative-Strand Synthesis.

Bakovic, Allison / Bhalla, Nishank / Kortchak, Stephanie / Sun, Chengqun / Zhou, Weidong / Ahmed, Aslaa / Risner, Kenneth / Klimstra, William B / Narayanan, Aarthi

Viruses

2020 Volume 12, Issue 9

Abstract: Venezuelan equine encephalitis virus (VEEV), a mosquito transmitted alphavirus of ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV), a mosquito transmitted alphavirus of the
MeSH term(s)	Aedes ; Animals ; Antiviral Agents/pharmacology ; Cell Line ; Chlorocebus aethiops ; Encephalitis Virus, Venezuelan Equine/drug effects ; Encephalitis Virus, Venezuelan Equine/genetics ; Encephalitis Virus, Venezuelan Equine/metabolism ; Encephalomyelitis, Venezuelan Equine ; Humans ; I-kappa B Kinase/metabolism ; Mutation ; NF-kappa B/metabolism ; Phosphorylation ; Vero Cells ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; NF-kappa B ; Viral Nonstructural Proteins ; I-kappa B Kinase (EC 2.7.11.10)
Language	English
Publishing date	2020-09-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12091021
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells.

Keck, Forrest / Kortchak, Stephanie / Bakovic, Allison / Roberts, Brian / Agrawal, Nitin / Narayanan, Aarthi

Virulence

2018 Volume 9, Issue 1, Page(s) 1403–1421

Abstract: Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that eventually contributes to neurodegenerative phenotypes. In this study, we utilize the TC-83 strain of VEEV, which is known to induce the expression of IL-6, IL-8, and other pro-inflammatory cytokines. We had previously demonstrated that TC-83 infection resulted in changes in mitochondrial function, eventually resulting in mitophagy. In this manuscript, we provide data that links upstream mitochondrial dysfunction with downstream pro-inflammatory cytokine production in the context of microglia and astrocytoma cells. We also provide data on the role of bystander cells, which significantly contribute to the overall inflammatory load. Use of a mitochondrial-targeted antioxidant, mitoquinone mesylate, greatly reduced the inflammatory cytokine load and ameliorated bystander cell inflammatory responses more significantly than a broad-spectrum anti-inflammatory compound (BAY 11-7082). Our data suggest that the inflammatory mediators, especially IL-1β, may prime naïve cells to infection and lead to increased infection rates in microglial and astrocytoma cells. Cumulatively, our data suggest that the interplay between mitochondrial dysfunction and inflammatory events elicited in a neuronal microenvironment during a TC-83 infection may contribute to the spread of infection.
MeSH term(s)	Animals ; Astrocytes/immunology ; Astrocytes/virology ; Astrocytoma/immunology ; Astrocytoma/virology ; Cell Line, Tumor ; Cytokines/immunology ; Encephalitis Virus, Venezuelan Equine/immunology ; Encephalomyelitis, Venezuelan Equine/immunology ; Humans ; Inflammation ; Membrane Potential, Mitochondrial ; Microglia/immunology ; Microglia/virology ; Mitochondria/drug effects ; Mitochondria/immunology ; Mitochondria/pathology ; Neuroglia/immunology ; Organophosphorus Compounds/pharmacology ; Ubiquinone/analogs & derivatives ; Ubiquinone/pharmacology
Chemical Substances	Cytokines ; Organophosphorus Compounds ; Ubiquinone (1339-63-5) ; mitoquinone (47BYS17IY0)
Language	English
Publishing date	2018-08-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2657572-3
ISSN	2150-5608 ; 2150-5594
ISSN (online)	2150-5608
ISSN	2150-5594
DOI	10.1080/21505594.2018.1509668
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Venezuelan Equine Encephalitis Virus nsP3 Phosphorylation Can Be Mediated by IKKβ Kinase Activity and Abrogation of Phosphorylation Inhibits Negative-Strand Synthesis

Bakovic, Allison / Bhalla, Nishank / Kortchak, Stephanie / Sun, Chengqun / Zhou, Weidong / Ahmed, Aslaa / Risner, Kenneth / Klimstra, William B / Narayanan, Aarthi

Viruses. 2020 Sept. 13, v. 12, no. 9

2020

Abstract: Venezuelan equine encephalitis virus (VEEV), a mosquito transmitted alphavirus of the Togaviridae family, can cause a highly inflammatory and encephalitic disease upon infection. Although a category B select agent, no FDA-approved vaccines or ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV), a mosquito transmitted alphavirus of the Togaviridae family, can cause a highly inflammatory and encephalitic disease upon infection. Although a category B select agent, no FDA-approved vaccines or therapeutics against VEEV currently exist. We previously demonstrated NF-κB activation and macromolecular reorganization of the IKK complex upon VEEV infection in vitro, with IKKβ inhibition reducing viral replication. Mass spectrometry and confocal microscopy revealed an interaction between IKKβ and VEEV non-structural protein 3 (nsP3). Here, using western blotting, a cell-free kinase activity assay, and mass spectrometry, we demonstrate that IKKβ kinase activity can directly phosphorylate VEEV nsP3 at sites 204/5, 142, and 134/5. Alanine substitution mutations at sites 204/5, 142, or 134/5 reduced VEEV replication by >30-100,000-fold corresponding to a severe decrease in negative-strand synthesis. Serial passaging rescued viral replication and negative-strand synthesis, and sequencing of revertant viruses revealed reversion to the wild-type TC-83 phosphorylation capable amino acid sequences at nsP3 sites 204/5, 142, and 135. Generation of phosphomimetic mutants using aspartic acid substitutions at site 204/5 resulted in rescue of both viral replication and negative-strand RNA production, whereas phosphomimetic mutant 134/5 rescued viral replication but failed to restore negative-strand RNA levels, and phosphomimetic mutant 142 did not rescue VEEV replication. Together, these data demonstrate that IKKβ can phosphorylate VEEV nsP3 at sites 204/5, 142, and 134/5, and suggest that phosphorylation is essential for negative-strand RNA synthesis at site 204/5, but may be important for infectious particle production at site 134/5.
Keywords	Culicidae ; RNA ; Venezuelan equine encephalitis virus ; Western blotting ; alanine ; amino acid sequences ; aspartic acid ; confocal microscopy ; enzyme activity ; enzymes ; mass spectrometry ; mutants ; mutation ; phosphorylation ; therapeutics ; transcription factor NF-kappa B ; vaccines ; viral nonstructural proteins ; virus replication ; viruses
Language	English
Dates of publication	2020-0913
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v12091021
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Maraviroc inhibits SARS-CoV-2 multiplication and s-protein mediated cell fusion in cell culture

Risner, Kenneth / Tieu, Katie V / Wang, Yafei / Bakovic, Allison / Bhalla, Nishank / Nathan, Steven / Conway, Daniel E / Macklin, Paul / Narayanan, Aarthi

bioRxiv

Abstract	In an effort to identify therapeutic intervention strategies for the treatment of COVID-19, we have investigated a selection of FDA-approved small molecules and biologics that are commonly used to treat other human diseases. A screen of 19 small molecules and 3 biologics was conducted in cell culture and the impact of treatment on viral titer was quantified by plaque assay. The screen identified 4 FDA-approved small molecules, Maraviroc, FTY720 (Fingolimod), Atorvastatin and Nitazoxanide that were able to inhibit SARS-CoV-2 infection. Confocal microscopy with over expressed S protein demonstrated that Maraviroc reduced the extent of S-protein mediated cell fusion as observed by fewer multinucleate cells in drug-treated cells. Mathematical modeling of drug-dependent viral multiplication dynamics revealed that prolonged drug treatment will exert an exponential decrease in viral load in a multicellular/tissue environment. Taken together, the data demonstrate that Maraviroc, Fingolimod, Atorvastatin and Nitazoxanide inhibit SARS-CoV-2 in cell culture.
Keywords	covid19
Language	English
Publishing date	2020-08-13
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.08.12.246389
Database	COVID19

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