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Article ; Online: Addressing the selectivity and toxicity of antiviral nucleosides.

Feng, Joy Y

2018 Volume 26, Page(s) 2040206618758524

Abstract: Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and ... ...

Abstract	Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/toxicity ; Humans ; Molecular Structure ; Nucleosides/pharmacology ; Nucleosides/toxicity ; Toxicity Tests ; Viruses/drug effects
Chemical Substances	Antiviral Agents ; Nucleosides
Keywords	covid19
Language	English
Publishing date	2018-03-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1033586-9
ISSN	2040-2066 ; 0956-3202
ISSN (online)	2040-2066
ISSN	0956-3202
DOI	10.1177/2040206618758524
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Article: HCV RdRp, sofosbuvir and beyond.

Feng, Joy Y / Ray, Adrian S

The Enzymes

2021 Volume 49, Page(s) 63–82

Abstract: The therapeutic targeting of the nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of the Hepatitis C Virus (HCV) with nucleotide analogs led to a deep understanding of this enzymes structure, function and substrate specificity. Unlike ... ...

Abstract	The therapeutic targeting of the nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of the Hepatitis C Virus (HCV) with nucleotide analogs led to a deep understanding of this enzymes structure, function and substrate specificity. Unlike previously studied DNA polymerases including the reverse transcriptase of Human Immunodeficiency Virus, development of biochemical assays for HCV RdRp proved challenging due to low solubility of the full-length protein and inefficient acceptance of exogenous primer/templates. Despite the poor apparent specific activity, HCV RdRp was found to support rapid and processive transcription once elongation is initiated in vitro consistent with its high level of viral replication in the livers of patients. Understanding of the substrate specificity of HCV RdRp led to the discovery of the active triphosphate of sofosbuvir as a nonobligate chain-terminator of viral RNA transcripts. The ternary crystal structure of HCV RdRp, primer/template, and incoming nucleotide showed the interaction between the nucleotide analog and the 2'-hydroxyl binding pocket and how an unfit mutation of serine 282 to threonine results in resistance by interacting with the uracil base and modified 2'-position of the analog. Host polymerases mediate off-target toxicity of nucleotide analogs and the active metabolite of sofosbuvir was found to not be efficiently incorporated by host polymerases including the mitochondrial RNA polymerase (POLRMT). Knowledge from studying inhibitors of HCV RdRp serves to advance antiviral drug discovery for other emerging RNA viruses including the discovery of remdesivir as an inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the virus that causes COVID-19.
MeSH term(s)	Hepacivirus/drug effects ; Hepacivirus/enzymology ; RNA, Viral ; RNA-Dependent RNA Polymerase/genetics ; SARS-CoV-2 ; Sofosbuvir/pharmacology ; Viral Nonstructural Proteins/antagonists & inhibitors
Chemical Substances	RNA, Viral ; Viral Nonstructural Proteins ; NS-5 protein, hepatitis C virus (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Sofosbuvir (WJ6CA3ZU8B)
Language	English
Publishing date	2021-09-24
Publishing country	United States
Document type	Journal Article
ISSN	0423-2607
ISSN	0423-2607
DOI	10.1016/bs.enz.2021.06.003
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Article ; Online: Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir.

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

Viruses

2019 Volume 11, Issue 4

Abstract: Remdesivir (GS-5734) is a 1'-cyano-substituted adenosine nucleotide analogue prodrug that shows broad-spectrum antiviral activity against several RNA viruses. This compound is currently under clinical development for the treatment of Ebola virus disease ( ...

Abstract	Remdesivir (GS-5734) is a 1'-cyano-substituted adenosine nucleotide analogue prodrug that shows broad-spectrum antiviral activity against several RNA viruses. This compound is currently under clinical development for the treatment of Ebola virus disease (EVD). While antiviral effects have been demonstrated in cell culture and in non-human primates, the mechanism of action of Ebola virus (EBOV) inhibition for remdesivir remains to be fully elucidated. The EBOV RNA-dependent RNA polymerase (RdRp) complex was recently expressed and purified, enabling biochemical studies with the relevant triphosphate (TP) form of remdesivir and its presumptive target. In this study, we confirmed that remdesivir-TP is able to compete for incorporation with adenosine triphosphate (ATP). Enzyme kinetics revealed that EBOV RdRp and respiratory syncytial virus (RSV) RdRp incorporate ATP and remdesivir-TP with similar efficiencies. The selectivity of ATP against remdesivir-TP is ~4 for EBOV RdRp and ~3 for RSV RdRp. In contrast, purified human mitochondrial RNA polymerase (h-mtRNAP) effectively discriminates against remdesivir-TP with a selectivity value of ~500-fold. For EBOV RdRp, the incorporated inhibitor at position i does not affect the ensuing nucleotide incorporation event at position i+1. For RSV RdRp, we measured a ~6-fold inhibition at position i+1 although RNA synthesis was not terminated. Chain termination was in both cases delayed and was seen predominantly at position i+5. This pattern is specific to remdesivir-TP and its 1'-cyano modification. Compounds with modifications at the 2'-position show different patterns of inhibition. While 2'-C-methyl-ATP is not incorporated, ara-ATP acts as a non-obligate chain terminator and prevents nucleotide incorporation at position i+1. Taken together, our biochemical data indicate that the major contribution to EBOV RNA synthesis inhibition by remdesivir can be ascribed to delayed chain termination. The long distance of five residues between the incorporated nucleotide analogue and its inhibitory effect warrant further investigation.
MeSH term(s)	Adenosine/analogs & derivatives ; Adenosine/chemistry ; Adenosine/metabolism ; Adenosine/pharmacology ; Adenosine Triphosphate/metabolism ; Alanine/analogs & derivatives ; Alanine/chemistry ; Alanine/metabolism ; Alanine/pharmacology ; Antiviral Agents/chemistry ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; DNA-Directed RNA Polymerases/metabolism ; Ebolavirus/enzymology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Kinetics ; Molecular Structure ; Prodrugs ; RNA Replicase/antagonists & inhibitors ; RNA Replicase/metabolism ; RNA, Viral/biosynthesis ; Respiratory Syncytial Virus, Human/drug effects ; Respiratory Syncytial Virus, Human/enzymology ; Respiratory Syncytial Virus, Human/physiology ; Ribonucleotides/chemistry ; Ribonucleotides/metabolism ; Ribonucleotides/pharmacology ; Substrate Specificity ; Viral Proteins/antagonists & inhibitors ; Viral Proteins/metabolism
Chemical Substances	Antiviral Agents ; Enzyme Inhibitors ; Prodrugs ; RNA, Viral ; Ribonucleotides ; Viral Proteins ; remdesivir (3QKI37EEHE) ; Adenosine Triphosphate (8L70Q75FXE) ; RNA Replicase (EC 2.7.7.48) ; DNA-Directed RNA Polymerases (EC 2.7.7.6) ; Adenosine (K72T3FS567) ; Alanine (OF5P57N2ZX)
Keywords	covid19
Language	English
Publishing date	2019-04-04
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/v11040326
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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: 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: Efficient incorporation and template-dependent polymerase inhibition are major determinants for the broad-spectrum antiviral activity of remdesivir.

Gordon, Calvin J / Lee, Hery W / Tchesnokov, Egor P / Perry, Jason K / Feng, Joy Y / Bilello, John P / Porter, Danielle P / Götte, Matthias

The Journal of biological chemistry

2021 Volume 298, Issue 2, Page(s) 101529

Abstract: Remdesivir (RDV) is a direct-acting antiviral agent that is approved in several countries for the treatment of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2. RDV exhibits broad-spectrum antiviral activity against ... ...

Abstract	Remdesivir (RDV) is a direct-acting antiviral agent that is approved in several countries for the treatment of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2. RDV exhibits broad-spectrum antiviral activity against positive-sense RNA viruses, for example, severe acute respiratory syndrome coronavirus and hepatitis C virus, and nonsegmented negative-sense RNA viruses, for example, Nipah virus, whereas segmented negative-sense RNA viruses such as influenza virus or Crimean-Congo hemorrhagic fever virus are not sensitive to the drug. The reasons for this apparent efficacy pattern are unknown. Here, we expressed and purified representative RNA-dependent RNA polymerases and studied three biochemical parameters that have been associated with the inhibitory effects of RDV-triphosphate (TP): (i) selective incorporation of the nucleotide substrate RDV-TP, (ii) the effect of the incorporated RDV-monophosphate (MP) on primer extension, and (iii) the effect of RDV-MP in the template during incorporation of the complementary UTP. We found a strong correlation between antiviral effects and efficient incorporation of RDV-TP. Inhibition in primer extension reactions was heterogeneous and usually inefficient at higher NTP concentrations. In contrast, template-dependent inhibition of UTP incorporation opposite the embedded RDV-MP was seen with all polymerases. Molecular modeling suggests a steric conflict between the 1'-cyano group of the inhibitor and residues of the structurally conserved RNA-dependent RNA polymerase motif F. We conclude that future efforts in the development of nucleotide analogs with a broader spectrum of antiviral activities should focus on improving rates of incorporation while capitalizing on the inhibitory effects of a bulky 1'-modification.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/chemistry ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/chemistry ; Alanine/pharmacology ; Antiviral Agents/pharmacology ; Hepacivirus/drug effects ; Hepacivirus/enzymology ; Models, Molecular ; Negative-Sense RNA Viruses/drug effects ; Negative-Sense RNA Viruses/enzymology ; Nipah Virus/drug effects ; Nipah Virus/enzymology ; Positive-Strand RNA Viruses/drug effects ; Positive-Strand RNA Viruses/enzymology ; RNA Viruses/drug effects ; RNA Viruses/enzymology ; RNA, Viral/metabolism ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; RNA-Dependent RNA Polymerase/chemistry ; RNA-Dependent RNA Polymerase/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; RNA, Viral ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2021-12-23
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	10.1016/j.jbc.2021.101529
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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 ; Online: An atomistic model of the coronavirus replication-transcription complex as a hexamer assembled around nsp15.

Perry, Jason K / Appleby, Todd C / Bilello, John P / Feng, Joy Y / Schmitz, Uli / Campbell, Elizabeth A

The Journal of biological chemistry

2021 Volume 297, Issue 4, Page(s) 101218

Abstract: The SARS-CoV-2 replication-transcription complex is an assembly of nonstructural viral proteins that collectively act to reproduce the viral genome and generate mRNA transcripts. While the structures of the individual proteins involved are known, how ... ...

Abstract	The SARS-CoV-2 replication-transcription complex is an assembly of nonstructural viral proteins that collectively act to reproduce the viral genome and generate mRNA transcripts. While the structures of the individual proteins involved are known, how they assemble into a functioning superstructure is not. Applying molecular modeling tools, including protein-protein docking, to the available structures of nsp7-nsp16 and the nucleocapsid, we have constructed an atomistic model of how these proteins associate. Our principal finding is that the complex is hexameric, centered on nsp15. The nsp15 hexamer is capped on two faces by trimers of nsp14/nsp16/(nsp10)
MeSH term(s)	Binding Sites ; COVID-19/pathology ; COVID-19/virology ; Dimerization ; Endoribonucleases/chemistry ; Endoribonucleases/genetics ; Endoribonucleases/metabolism ; Humans ; Models, Molecular ; Molecular Docking Simulation ; Protein Structure, Quaternary ; RNA, Double-Stranded/chemistry ; RNA, Double-Stranded/metabolism ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/metabolism ; Transcription, Genetic ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism ; Virus Replication
Chemical Substances	RNA, Double-Stranded ; Viral Nonstructural Proteins ; Endoribonucleases (EC 3.1.-) ; nidoviral uridylate-specific endoribonuclease (EC 3.1.-)
Language	English
Publishing date	2021-09-23
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	10.1016/j.jbc.2021.101218
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Article ; Online: Role of Mitochondrial Toxicity in BMS-986094-Induced Toxicity.

Feng, Joy Y / Tay, Chin H / Ray, Adrian S

Toxicological sciences : an official journal of the Society of Toxicology

2016 Volume 155, Issue 1, Page(s) 2

MeSH term(s)	DNA, Mitochondrial ; Dose-Response Relationship, Drug ; Guanosine ; Guanosine Monophosphate/analogs & derivatives
Chemical Substances	DNA, Mitochondrial ; Guanosine (12133JR80S) ; BMS-986094 (62F4AD749Y) ; Guanosine Monophosphate (85-32-5)
Language	English
Publishing date	2016-11-01
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfw224
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