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Article ; Online: Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template.

Gordon, Calvin J / Tchesnokov, Egor P / Schinazi, Raymond F / Götte, Matthias

2021 Volume 297, Issue 1, Page(s) 100770

Abstract: The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 is an important target in current drug development efforts for the treatment of coronavirus disease 2019. Molnupiravir is a broad-spectrum antiviral that is an orally ...

Abstract	The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 is an important target in current drug development efforts for the treatment of coronavirus disease 2019. Molnupiravir is a broad-spectrum antiviral that is an orally bioavailable prodrug of the nucleoside analogue β-D-N
MeSH term(s)	Antiviral Agents/pharmacology ; COVID-19/virology ; Cytidine/analogs & derivatives ; Cytidine/pharmacology ; Humans ; Hydroxylamines/pharmacology ; Mutagenesis ; Point Mutation/drug effects ; RNA, Viral/genetics ; SARS-CoV-2/drug effects ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism
Chemical Substances	Antiviral Agents ; Hydroxylamines ; RNA, Viral ; Cytidine (5CSZ8459RP) ; N(4)-hydroxycytidine (C3D11PV2O4) ; molnupiravir (YA84KI1VEW)
Language	English
Publishing date	2021-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.100770
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Article ; Online: Correction: Template-dependent inhibition of coronavirus RNA-dependent RNA polymerase by remdesivir reveals a second mechanism of action.

Tchesnokov, Egor P / Gordon, Calvin J / Woolner, Emma / Kocincova, Dana / Perry, Jason K / Feng, Joy Y / Porter, Danielle P / Götte, Matthias

The Journal of biological chemistry

2021 Volume 297, Issue 2, Page(s) 101048

Language	English
Publishing date	2021-08-06
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.101048
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Article: Inhibition of viral RNA-dependent RNA polymerases with clinically relevant nucleotide analogs.

Maheden, Kieran / Todd, Brendan / Gordon, Calvin J / Tchesnokov, Egor P / Götte, Matthias

The Enzymes

2021 Volume 49, Page(s) 315–354

Abstract: The treatment of viral infections remains challenging, in particular in the face of emerging pathogens. Broad-spectrum antiviral drugs could potentially be used as a first line of defense. The RNA-dependent RNA polymerase (RdRp) of RNA viruses serves as ... ...

Abstract	The treatment of viral infections remains challenging, in particular in the face of emerging pathogens. Broad-spectrum antiviral drugs could potentially be used as a first line of defense. The RNA-dependent RNA polymerase (RdRp) of RNA viruses serves as a logical target for drug discovery and development efforts. Herein we discuss compounds that target RdRp of poliovirus, hepatitis C virus, influenza viruses, respiratory syncytial virus, and the growing data on coronaviruses. We focus on nucleotide analogs and mechanisms of action and resistance.
MeSH term(s)	Antiviral Agents/pharmacology ; Nucleotides/pharmacology ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Viral Replicase Complex Proteins/antagonists & inhibitors ; Virus Replication ; Viruses/enzymology
Chemical Substances	Antiviral Agents ; Nucleotides ; Viral Replicase Complex Proteins ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2021-10-15
Publishing country	United States
Document type	Journal Article
ISSN	0423-2607
ISSN	0423-2607
DOI	10.1016/bs.enz.2021.07.002
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Clinical Features of COVID-19 Infection in Patients Treated at a Large Veterans Affairs Medical Center.

Ebert, Thomas J / Dugan, Shannon / Barta, Lauren / Gordon, Brian / Nguyen-Ho, Calvin / Pagel, Paul S

WMJ : official publication of the State Medical Society of Wisconsin

2021 Volume 119, Issue 4, Page(s) 248–252

Abstract: Introduction: During recent months, reports describing the characteristics of COVID-19 patients in China, Italy, and the United States have been published. Military veterans represent another unique population affected by COVID-19. This report ... ...

Abstract	Introduction: During recent months, reports describing the characteristics of COVID-19 patients in China, Italy, and the United States have been published. Military veterans represent another unique population affected by COVID-19. This report summarizes the demographics and baseline clinical comorbidities in veterans testing positive for COVID-19 in Milwaukee, Wisconsin. Methods: Patient evaluations were conducted at the Zablocki VA Medical Center, Milwaukee, Wisconsin between March 11, 2020 and June 1, 2020. Patient demographics, baseline comorbidities, home medications, presenting symptoms, and outcomes were obtained via electronic medical record. Results: Ninety-five patients (88 men, 7 women) tested positive for COVID-19 and were evaluated. Fourteen required mechanical ventilation; 50 and 31 patients were treated in the hospital without ventilation or were discharged to home isolation, respectively. Discharged patients were younger than patients hospitalized. Most patients with COVID-19 were African American (63.2%). Patients whose disease progressed to mechanical ventilation had, on admission, more dyspnea, higher heart and respiratory rates, and lower oxygen saturation than other patients. COVID-19 patients who required mechanical ventilation had a longer length of stay and higher mortality than other groups and were more likely to have a history of hypertension and hyperlipidemia than patients who were discharged to home quarantine (85.7% and 78.6% vs 48.4% and 45.2%, respectively; P < 0.05 for each). Conclusion: COVID-19-positive veterans are predominantly African American men with hypertension and hyperlipidemia receiving beta blockers or ACEi/ARB. COVID-19-positive veterans who presented with dyspnea, tachypnea, tachycardia, and hypoxemia were more likely to require endotracheal intubation and mechanical ventilation, had longer hospital length-of-stay, and experienced greater mortality than comparison groups.
MeSH term(s)	Adult ; Aged ; COVID-19/epidemiology ; COVID-19/therapy ; Comorbidity ; Female ; Hospitals, Veterans ; Humans ; Male ; Middle Aged ; Pandemics ; United States/epidemiology ; Veterans ; Wisconsin/epidemiology
Language	English
Publishing date	2021-01-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	441051-8
ISSN	2379-3961 ; 0043-6542 ; 1098-1861
ISSN (online)	2379-3961
ISSN	0043-6542 ; 1098-1861
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mechanism and spectrum of inhibition of a 4’-cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses

Gordon, Calvin J. / Walker, Simon M. / Tchesnokov, Egor P. / Kocincova, Dana / Pitts, Jared / Siegel, Dustin S. / Perry, Jason K. / Feng, Joy Y. / Bilello, John P. / Götte, Matthias

bioRxiv

Abstract: The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide ... ...

Abstract	The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRp) of prototypic respiratory viruses. GS-646939 is the active 5′-triphosphate (TP) metabolite of a 4ʹ-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 (EV-71) incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase (h-mtRNAP) does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain-terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4ʹ-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1′-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1ʹ-cyano and 4ʹ-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.
Keywords	covid19
Language	English
Publishing date	2024-04-23
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.04.22.590607
Database	COVID19

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Article ; Online: Mechanism and spectrum of inhibition of a 4′-cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses

Gordon, Calvin J. / Walker, Simon M. / Tchesnokov, Egor P. / Kocincova, Dana / Pitts, Jared / Siegel, Dustin S. / Perry, Jason K. / Feng, Joy Y. / Bilello, John P. / Gotte, Matthias

bioRxiv

Abstract	The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRp) of prototypic respiratory viruses. GS-646939 is the active 5′-triphosphate (TP) metabolite of a 4ʹ-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 (EV-71) incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase (h-mtRNAP) does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain-terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4ʹ-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1′-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1ʹ-cyano and 4ʹ-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.
Keywords	covid19
Language	English
Publishing date	2024-04-23
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.04.22.590607
Database	COVID19

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Article ; Online: Evolution of naturally arising SARS-CoV-2 defective interfering particles.

Girgis, Samer / Xu, Zaikun / Oikonomopoulos, Spyros / Fedorova, Alla D / Tchesnokov, Egor P / Gordon, Calvin J / Schmeing, T Martin / Götte, Matthias / Sonenberg, Nahum / Baranov, Pavel V / Ragoussis, Jiannis / Hobman, Tom C / Pelletier, Jerry

Communications biology

2022 Volume 5, Issue 1, Page(s) 1140

Abstract: Defective interfering (DI) particles arise during virus propagation, are conditional on parental virus for replication and packaging, and interfere with viral expansion. There is much interest in developing DIs as anti-viral agents. Here we characterize ... ...

Abstract	Defective interfering (DI) particles arise during virus propagation, are conditional on parental virus for replication and packaging, and interfere with viral expansion. There is much interest in developing DIs as anti-viral agents. Here we characterize DI particles that arose following serial passaging of SARS-CoV-2 at high multiplicity of infection. The prominent DIs identified have lost ~84% of the SARS-CoV-2 genome and are capable of attenuating parental viral titers. Synthetic variants of the DI genomes also interfere with infection and can be used as conditional, gene delivery vehicles. In addition, the DI genomes encode an Nsp1-10 fusion protein capable of attenuating viral replication. These results identify naturally selected defective viral genomes that emerged and stably propagated in the presence of parental virus.
MeSH term(s)	Humans ; Defective Viruses/genetics ; SARS-CoV-2/genetics ; Defective Interfering Viruses ; RNA, Viral/genetics ; COVID-19
Chemical Substances	RNA, Viral
Language	English
Publishing date	2022-10-27
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-04058-5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus.

Gordon, Calvin J / Tchesnokov, Egor P / Feng, Joy Y / Porter, Danielle P / Götte, Matthias

The Journal of biological chemistry

2020 Volume 295, Issue 15, Page(s) 4773–4779

Abstract: Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome-coronavirus 2 (CoV-2). Remdesivir (RDV) is ... ...

Abstract	Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome-coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/chemistry ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/chemistry ; Alanine/pharmacology ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Coronavirus/enzymology ; Ebolavirus/enzymology ; Gene Expression ; Middle East Respiratory Syndrome Coronavirus/enzymology ; Nucleic Acid Synthesis Inhibitors/chemistry ; Nucleic Acid Synthesis Inhibitors/pharmacology ; RNA ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; RNA-Dependent RNA Polymerase/genetics ; Sf9 Cells ; Viral Nonstructural Proteins/genetics ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Nucleic Acid Synthesis Inhibitors ; RNA primers ; Viral Nonstructural Proteins ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; RNA (63231-63-0) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Alanine (OF5P57N2ZX)
Keywords	covid19
Language	English
Publishing date	2020-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.AC120.013056
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Article ; Online: Evolution of naturally arising SARS-CoV-2 defective interfering particles

Samer Girgis / Zaikun Xu / Spyros Oikonomopoulos / Alla D. Fedorova / Egor P. Tchesnokov / Calvin J. Gordon / T. Martin Schmeing / Matthias Götte / Nahum Sonenberg / Pavel V. Baranov / Jiannis Ragoussis / Tom C. Hobman / Jerry Pelletier

Communications Biology, Vol 5, Iss 1, Pp 1-

2022 Volume 12

Abstract: Genomes from defective interfering (DI) particles following serial passaging of SARS-CoV-2 reveal a fusion protein that attenuates viral replication. Synthetic, recombinant DI genomes are designed to interfere with SARS-CoV-2 replication. ...

Abstract	Genomes from defective interfering (DI) particles following serial passaging of SARS-CoV-2 reveal a fusion protein that attenuates viral replication. Synthetic, recombinant DI genomes are designed to interfere with SARS-CoV-2 replication.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS.

Niezen, Sebastian / Connelly, Margery A / Hirsch, Calvin / Kizer, Jorge R / Benitez, Maria E / Minchenberg, Scott / Perez-Matos, Maria Camila / Jiang, Zhenghui Gordon / Mukamal, Kenneth J

Journal of the American Heart Association

2023 Volume 12, Issue 17, Page(s) e029960

Abstract: Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the ...

Abstract	Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0-1.9];
MeSH term(s)	Humans ; Aged ; Incidence ; Heart Failure/diagnosis ; Heart Failure/epidemiology ; Cardiovascular Diseases ; Aging ; Ketone Bodies
Chemical Substances	Ketone Bodies
Language	English
Publishing date	2023-08-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.123.029960
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