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Article ; Online: Inhibitors of the Ubiquitin-Mediated Signaling Pathway Exhibit Broad-Spectrum Antiviral Activities against New World Alphaviruses.

Boghdeh, Niloufar A / McGraw, Brittany / Barrera, Michael D / Anderson, Carol / Baha, Haseebullah / Risner, Kenneth H / Ogungbe, Ifedayo V / Alem, Farhang / Narayanan, Aarthi

Viruses

2023 Volume 15, Issue 3

Abstract: New World alphaviruses including Venezuelan Equine Encephalitis Virus (VEEV) and Eastern Equine Encephalitis Virus (EEEV) are mosquito-transmitted viruses that cause disease in humans and equines. There are currently no FDA-approved therapeutics or ... ...

Abstract	New World alphaviruses including Venezuelan Equine Encephalitis Virus (VEEV) and Eastern Equine Encephalitis Virus (EEEV) are mosquito-transmitted viruses that cause disease in humans and equines. There are currently no FDA-approved therapeutics or vaccines to treat or prevent exposure-associated encephalitic disease. The ubiquitin proteasome system (UPS)-associated signaling events are known to play an important role in the establishment of a productive infection for several acutely infectious viruses. The critical engagement of the UPS-associated signaling mechanisms by many viruses as host-pathogen interaction hubs led us to hypothesize that small molecule inhibitors that interfere with these signaling pathways will exert broad-spectrum inhibitory activity against alphaviruses. We queried eight inhibitors of the UPS signaling pathway for antiviral outcomes against VEEV. Three of the tested inhibitors, namely NSC697923 (NSC), bardoxolone methyl (BARM) and omaveloxolone (OMA) demonstrated broad-spectrum antiviral activity against VEEV and EEEV. Dose dependency and time of addition studies suggest that BARM and OMA exhibit intracellular and post-entry viral inhibition. Cumulatively, our studies indicate that inhibitors of the UPS-associated signaling pathways exert broad-spectrum antiviral outcomes in the context of VEEV and EEEV infection, supporting their translational application as therapeutic candidates to treat alphavirus infections.
MeSH term(s)	Humans ; Horses ; Animals ; Alphavirus ; Antiviral Agents/pharmacology ; Ubiquitin ; Encephalitis Virus, Venezuelan Equine ; Signal Transduction
Chemical Substances	Antiviral Agents ; Ubiquitin
Language	English
Publishing date	2023-02-28
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/v15030655
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: 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
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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
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Article ; Online: Application of a Human Blood Brain Barrier Organ-on-a-Chip Model to Evaluate Small Molecule Effectiveness against Venezuelan Equine Encephalitis Virus.

Boghdeh, Niloufar A / Risner, Kenneth H / Barrera, Michael D / Britt, Clayton M / Schaffer, David K / Alem, Farhang / Brown, Jacquelyn A / Wikswo, John P / Narayanan, Aarthi

Viruses

2022 Volume 14, Issue 12

Abstract: The blood brain barrier (BBB) is a multicellular microenvironment that plays an important role in regulating bidirectional transport to and from the central nervous system (CNS). Infections by many acutely infectious viruses such as alphaviruses and ... ...

Abstract	The blood brain barrier (BBB) is a multicellular microenvironment that plays an important role in regulating bidirectional transport to and from the central nervous system (CNS). Infections by many acutely infectious viruses such as alphaviruses and flaviviruses are known to impact the integrity of the endothelial lining of the BBB. Infection by Venezuelan Equine Encephalitis Virus (VEEV) through the aerosol route causes significant damage to the integrity of the BBB, which contributes to long-term neurological sequelae. An effective therapeutic intervention strategy should ideally not only control viral load in the host, but also prevent and/or reverse deleterious events at the BBB. Two dimensional monocultures, including trans-well models that use endothelial cells, do not recapitulate the intricate multicellular environment of the BBB. Complex in vitro organ-on-a-chip models (OOC) provide a great opportunity to introduce human-like experimental models to understand the mechanistic underpinnings of the disease state and evaluate the effectiveness of therapeutic candidates in a highly relevant manner. Here we demonstrate the utility of a neurovascular unit (NVU) in analyzing the dynamics of infection and proinflammatory response following VEEV infection and therapeutic effectiveness of omaveloxolone to preserve BBB integrity and decrease viral and inflammatory load.
MeSH term(s)	Humans ; Animals ; Horses ; Encephalitis Virus, Venezuelan Equine/physiology ; Blood-Brain Barrier ; Encephalomyelitis, Venezuelan Equine/drug therapy ; Encephalomyelitis, Venezuelan Equine/prevention & control ; Endothelial Cells ; Microphysiological Systems
Language	English
Publishing date	2022-12-15
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/v14122799
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: 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: Synthetic Host Defense Peptides Inhibit Venezuelan Equine Encephalitis Virus Replication and the Associated Inflammatory Response.

Ahmed, Aslaa / Bakovic, Allison / Risner, Kenneth / Kortchak, Stephanie / Der Torossian Torres, Marcelo / de la Fuente-Nunez, Cesar / Lu, Timothy / Bhalla, Nishank / Narayanan, Aarthi

Scientific reports

2020 Volume 10, Issue 1, Page(s) 21491

Abstract: Venezuelan equine encephalitis virus (VEEV), a New World alphavirus of the Togaviridae family of viruses causes periodic outbreaks of disease in humans and equines. Disease following VEEV infection manifests as a febrile illness with flu-like symptoms, ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV), a New World alphavirus of the Togaviridae family of viruses causes periodic outbreaks of disease in humans and equines. Disease following VEEV infection manifests as a febrile illness with flu-like symptoms, which can progress to encephalitis and cause permanent neurological sequelae in a small number of cases. VEEV is classified as a category B select agent due to ease of aerosolization and high retention of infectivity in the aerosol form. Currently, there are no FDA-approved vaccines or therapeutics available to combat VEEV infection. VEEV infection in vivo is characterized by extensive systemic inflammation that can exacerbate infection by potentially increasing the susceptibility of off-site cells to infection and dissemination of the virus. Hence, a therapeutic targeting both the infection and associated inflammation represents an unmet need. We have previously demonstrated that host defense peptides (HDPs), short peptides that are key components of the innate immune response, exhibit antiviral activity against a multitude of viruses including VEEV. In this study, we designed synthetic peptides derived from indolicidin, a naturally occurring HDP, and tested their efficacy against VEEV. Two candidate synthetic peptides inhibited VEEV replication by approximately 1000-fold and decreased the expression of inflammatory mediators such as IL1α, IL1β, IFNγ, and TNFα at both the gene and protein expression levels. Furthermore, an increase in expression levels of genes involved in chemotaxis of leukocytes and anti-inflammatory genes such as IL1RN was also observed. Overall, we conclude that our synthetic peptides inhibit VEEV replication and the inflammatory burden associated with VEEV infection.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Antimicrobial Cationic Peptides/chemical synthesis ; Antimicrobial Cationic Peptides/chemistry ; Antimicrobial Cationic Peptides/pharmacology ; Antiviral Agents/pharmacology ; Cell Line ; Chlorocebus aethiops ; Disease Models, Animal ; Encephalitis Virus, Venezuelan Equine/genetics ; Encephalitis Virus, Venezuelan Equine/metabolism ; Horses ; Humans ; Inflammation ; Mice ; Vero Cells ; Virus Replication/drug effects
Chemical Substances	Anti-Inflammatory Agents ; Antimicrobial Cationic Peptides ; Antiviral Agents ; indolicidin (073SBV429N)
Language	English
Publishing date	2020-12-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-77990-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Brilacidin, a COVID-19 Drug Candidate, Exhibits Potent In Vitro Antiviral Activity Against SARS-CoV-2

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

bioRxiv

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 one 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 one 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 primarily a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin has demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 and thus supports brilacidin as a promising COVID-19 drug candidate. Highlights: Brilacidin potently inhibits SARS-CoV-2 in an ACE2 positive human lung cell line. Brilacidin achieved a high Selectivity Index of 426 (CC<sub>50</sub>=241µM/IC<sub>50</sub>=0.565µM). Brilacidin9s main mechanism appears to disrupt viral integrity and impact viral entry. Brilacidin and remdesivir exhibit excellent synergistic activity against SARS-CoV-2. Significance Statement: SARS-CoV-2, the emergent novel coronavirus, has led to the current global COVID-19 pandemic, characterized by extreme contagiousness and high mortality rates. There is an urgent need for effective therapeutic strategies to safely and effectively treat SARS-CoV-2 infection. We demonstrate that brilacidin, a synthetic small molecule with peptide-like properties, is capable of exerting potent in vitro antiviral activity against SARS-CoV-2, both as a standalone treatment and in combination with remdesivir, which is currently the only FDA-approved drug for the treatment of COVID-19.
Keywords	covid19
Language	English
Publishing date	2020-10-30
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.10.29.352450
Database	COVID19

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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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