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Article ; Online: Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1).

Hedskog, Charlotte / Rodriguez, Lauren / Roychoudhury, Pavitra / Huang, Meei-Li / Jerome, Keith R / Hao, Linhui / Ireton, Renee C / Li, Jiani / Perry, Jason K / Han, Dong / Camus, Gregory / Greninger, Alexander L / Gale, Michael / Porter, Danielle P

The Journal of infectious diseases

2023 Volume 228, Issue 9, Page(s) 1263–1273

Abstract: Background: Remdesivir is approved for treatment of coronavirus disease 2019 (COVID-19) in nonhospitalized and hospitalized adult and pediatric patients. Here we present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resistance analyses ... ...

Abstract	Background: Remdesivir is approved for treatment of coronavirus disease 2019 (COVID-19) in nonhospitalized and hospitalized adult and pediatric patients. Here we present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resistance analyses from the phase 3 ACTT-1 randomized placebo-controlled trial conducted in adult participants hospitalized with COVID-19. Methods: Swab samples were collected at baseline and longitudinally through day 29. SARS-CoV-2 genomes were sequenced using next-generation sequencing. Phenotypic analysis was conducted directly on participant virus isolates and/or using SARS-CoV-2 subgenomic replicons expressing mutations identified in the Nsp12 target gene. Results: Among participants with both baseline and postbaseline sequencing data, emergent Nsp12 substitutions were observed in 12 of 31 (38.7%) and 12 of 30 (40.0%) participants in the remdesivir and placebo arms, respectively. No emergent Nsp12 substitutions in the remdesivir arm were observed in more than 1 participant. Phenotyping showed low to no change in susceptibility to remdesivir relative to wild-type Nsp12 reference for the substitutions tested: A16V (0.8-fold change in EC50), P323L + V792I (2.2-fold), C799F (2.5-fold), K59N (1.0-fold), and K59N + V792I (3.4-fold). Conclusions: The similar rate of emerging Nsp12 substitutions in the remdesivir and placebo arms and the minimal change in remdesivir susceptibility among tested substitutions support a high barrier to remdesivir resistance development in COVID-19 patients. Clinical Trials Registration. NCT04280705.
MeSH term(s)	Adult ; Humans ; Child ; COVID-19 ; SARS-CoV-2/genetics ; COVID-19 Drug Treatment ; Adenosine Monophosphate/therapeutic use ; Alanine/therapeutic use ; Antiviral Agents/therapeutic use
Chemical Substances	remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Alanine (OF5P57N2ZX) ; Antiviral Agents
Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad270
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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: In Vitro

Checkmahomed, Liva / Carbonneau, Julie / Du Pont, Venice / Riola, Nicholas C / Perry, Jason K / Li, Jiani / Paré, Bastien / Simpson, Shawn M / Smith, Martin A / Porter, Danielle P / Boivin, Guy

Antimicrobial agents and chemotherapy

2022 Volume 66, Issue 7, Page(s) e0019822

Abstract: ... In ... ...

Abstract	In vitro
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/chemistry ; Alanine/analogs & derivatives ; Alanine/metabolism ; Antiviral Agents/chemistry ; COVID-19/drug therapy ; Humans ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2022-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.00198-22
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Article ; Online: Ensemble cryo-EM reveals conformational states of the nsp13 helicase in the SARS-CoV-2 helicase replication-transcription complex.

Chen, James / Wang, Qi / Malone, Brandon / Llewellyn, Eliza / Pechersky, Yakov / Maruthi, Kashyap / Eng, Ed T / Perry, Jason K / Campbell, Elizabeth A / Shaw, David E / Darst, Seth A

Nature structural & molecular biology

2022 Volume 29, Issue 3, Page(s) 250–260

Abstract: The SARS-CoV-2 nonstructural proteins coordinate genome replication and gene expression. Structural analyses revealed the basis for coupling of the essential nsp13 helicase with the RNA-dependent RNA polymerase (RdRp) where the holo-RdRp and RNA ... ...

Abstract	The SARS-CoV-2 nonstructural proteins coordinate genome replication and gene expression. Structural analyses revealed the basis for coupling of the essential nsp13 helicase with the RNA-dependent RNA polymerase (RdRp) where the holo-RdRp and RNA substrate (the replication-transcription complex or RTC) associated with two copies of nsp13 (nsp13
MeSH term(s)	COVID-19 ; Cryoelectron Microscopy ; Humans ; RNA Helicases/chemistry ; SARS-CoV-2 ; Viral Nonstructural Proteins/chemistry ; Virus Replication
Chemical Substances	Viral Nonstructural Proteins ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2022-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-022-00734-6
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Article ; Online: 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 / Kocinkova, Dana / Perry, Jason K / Feng, Joy Y / Porter, Danielle P / Götte, Matthias

The Journal of biological chemistry

2020 Volume 295, Issue 47, Page(s) 16156–16165

Abstract: Remdesivir (RDV) is a direct-acting antiviral agent that is used to treat patients with severe coronavirus disease 2019 (COVID-19). RDV targets the viral RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ...

Abstract	Remdesivir (RDV) is a direct-acting antiviral agent that is used to treat patients with severe coronavirus disease 2019 (COVID-19). RDV targets the viral RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have previously shown that incorporation of the active triphosphate form of RDV (RDV-TP) at position i causes delayed chain termination at position i + 3. Here we demonstrate that the S861G mutation in RdRp eliminates chain termination, which confirms the existence of a steric clash between Ser-861 and the incorporated RDV-TP. With WT RdRp, increasing concentrations of NTP pools cause a gradual decrease in termination and the resulting read-through increases full-length product formation. Hence, RDV residues could be embedded in copies of the first RNA strand that is later used as a template. We show that the efficiency of incorporation of the complementary UTP opposite template RDV is compromised, providing a second opportunity to inhibit replication. A structural model suggests that RDV, when serving as the template for the incoming UTP, is not properly positioned because of a significant clash with Ala-558. The adjacent Val-557 is in direct contact with the template base, and the V557L mutation is implicated in low-level resistance to RDV. We further show that the V557L mutation in RdRp lowers the nucleotide concentration required to bypass this template-dependent inhibition. The collective data provide strong evidence to show that template-dependent inhibition of SARS-CoV-2 RdRp by RDV is biologically relevant.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Antiviral Agents/pharmacology ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Coronavirus RNA-Dependent RNA Polymerase/chemistry ; Coronavirus RNA-Dependent RNA Polymerase/genetics ; Coronavirus RNA-Dependent RNA Polymerase/metabolism ; Models, Chemical ; Mutation ; Nucleotides/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; SARS-CoV-2/genetics ; Templates, Genetic ; Transcription Termination, Genetic/drug effects ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Nucleotides ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Alanine (OF5P57N2ZX)
Keywords	covid19
Language	English
Publishing date	2020-09-23
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	10.1074/jbc.AC120.015720
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Article ; Online: Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency.

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

The Journal of biological chemistry

2020 Volume 295, Issue 20, Page(s) 6785–6797

Abstract: Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA ... ...

Abstract	Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Animals ; Antiviral Agents/pharmacology ; Betacoronavirus/enzymology ; Betacoronavirus/physiology ; Models, Molecular ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; SARS-CoV-2 ; Sf9 Cells ; Spodoptera ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Alanine (OF5P57N2ZX)
Keywords	covid19
Language	English
Publishing date	2020-04-13
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.RA120.013679
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