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Article ; Online: Identification of Buffer Conditions for Optimal Thermostability and Solubility of Herpesviral Protein UL37 Using the Thermofluor Assay.

Koenigsberg, Andrea L / Pitts, Jared D / Heldwein, Ekaterina E

2020 Volume 10, Issue 12, Page(s) e3662

Abstract: Structural and biochemical studies of proteins require high amounts of stable, purified proteins. Protein stability often depends on the buffer composition, which includes pH and concentration of salts or other solutes such as glycerol, hence an ... ...

Abstract	Structural and biochemical studies of proteins require high amounts of stable, purified proteins. Protein stability often depends on the buffer composition, which includes pH and concentration of salts or other solutes such as glycerol, hence an efficient method for identifying optimal buffer conditions for stability would minimize time and resources used for protein purification and further studies. This protocol describes the use of the Thermofluor assay, in combination with a custom 24-condition screen, to identify buffer conditions that increase protein thermostability, using the conserved herpesviral protein UL37 as an example. Detailed instructions on screen conditions, running the Thermofluor MATLAB script, and analyzing the data are provided. In comparison to circular dichroism (CD), the buffer screen in combination with Thermofluor assay provides a faster and more informative method to analyze protein thermostability.
Language	English
Publishing date	2020-06-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.3662
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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: Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants.

Pitts, Jared / Li, Jiani / Perry, Jason K / Du Pont, Venice / Riola, Nicholas / Rodriguez, Lauren / Lu, Xianghan / Kurhade, Chaitanya / Xie, Xuping / Camus, Gregory / Manhas, Savrina / Martin, Ross / Shi, Pei-Yong / Cihlar, Tomas / Porter, Danielle P / Mo, Hongmei / Maiorova, Evguenia / Bilello, John P

Antimicrobial agents and chemotherapy

2022 Volume 66, Issue 6, Page(s) e0022222

Abstract: Genetic variation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence and rapid spread of multiple variants throughout the pandemic, of which Omicron is currently the predominant variant circulating worldwide. ... ...

Abstract	Genetic variation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence and rapid spread of multiple variants throughout the pandemic, of which Omicron is currently the predominant variant circulating worldwide. SARS-CoV-2 variants of concern/variants of interest (VOC/VOI) have evidence of increased viral transmission, disease severity, or decreased effectiveness of vaccines and neutralizing antibodies. Remdesivir (RDV [VEKLURY]) is a nucleoside analog prodrug and the first FDA-approved antiviral treatment of COVID-19. Here, we present a comprehensive antiviral activity assessment of RDV and its parent nucleoside, GS-441524, against 10 current and former SARS-CoV-2 VOC/VOI clinical isolates by nucleoprotein enzyme-linked immunosorbent assay (ELISA) and plaque reduction assay. Delta and Omicron variants remained susceptible to RDV and GS-441524, with 50% effective concentration (EC
MeSH term(s)	Adenosine/analogs & derivatives ; Adenosine Monophosphate/analogs & derivatives ; Alanine/analogs & derivatives ; Antiviral Agents/pharmacology ; COVID-19/drug therapy ; Humans ; SARS-CoV-2/genetics
Chemical Substances	Antiviral Agents ; GS-441524 (1BQK176DT6) ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Adenosine (K72T3FS567) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2022-05-09
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.00222-22
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Article ; Online: Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus.

Pitts, Jared D / Li, Pi-Chun / de Wispelaere, Melissanne / Yang, Priscilla L

Antiviral research

2017 Volume 147, Page(s) 124–130

Abstract: The rapid spread of Zika virus (ZIKV) in recent years has highlighted the severe diseases associated with ZIKV infection, such as Guillain-Barré syndrome in adults and microcephaly in newborns; yet no vaccines or antivirals currently exist to prevent or ... ...

Abstract	The rapid spread of Zika virus (ZIKV) in recent years has highlighted the severe diseases associated with ZIKV infection, such as Guillain-Barré syndrome in adults and microcephaly in newborns; yet no vaccines or antivirals currently exist to prevent or treat ZIKV infection. We and others have previously identified N-(4-hydroxyphenyl) retinamide (fenretinide or 4-HPR) as an antiviral compound that inhibits dengue virus 2 (DV2) and other flaviviruses by limiting the steady-state accumulation of viral RNA. Here we show that 4-HPR potently inhibits ZIKV in mammalian cell culture and significantly reduces both serum viremia and brain viral burden in a murine model of ZIKV infection. Consistent with previous observations with dengue virus, this antiviral activity is associated with a significant reduction in the steady-state abundance of viral genomic RNA. We show this reduction is due to a major decrease in the rate of viral RNA synthesis, though not via direct inhibition of the activity of the viral replicase. These results establish 4-HPR's mode of action against DV and ZIKV and, taken with previous clinical trials that established 4-HPR's safety and tolerability, illustrate the potential utility of 4-HPR as an agent for treatment of ZIKV infection.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Cell Line ; Dengue Virus/drug effects ; Disease Models, Animal ; Female ; Fenretinide/pharmacology ; Fenretinide/therapeutic use ; Humans ; Male ; Mice ; Mice, 129 Strain ; RNA, Viral/metabolism ; Viral Load/drug effects ; Viral Plaque Assay ; Virus Replication/drug effects ; Zika Virus/drug effects ; Zika Virus/growth & development ; Zika Virus Infection/drug therapy ; Zika Virus Infection/virology
Chemical Substances	Antiviral Agents ; RNA, Viral ; Fenretinide (187EJ7QEXL)
Language	English
Publishing date	2017-10-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2017.10.014
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Article ; Online: Inhaled remdesivir reduces viral burden in a nonhuman primate model of SARS-CoV-2 infection.

Vermillion, Meghan S / Murakami, Eisuke / Ma, Bin / Pitts, Jared / Tomkinson, Adrian / Rautiola, Davin / Babusis, Darius / Irshad, Hammad / Seigel, Dustin / Kim, Cynthia / Zhao, Xiaofeng / Niu, Congrong / Yang, Jesse / Gigliotti, Andrew / Kadrichu, Nani / Bilello, John P / Ellis, Scott / Bannister, Roy / Subramanian, Raju /

Smith, Bill / Mackman, Richard L / Lee, William A / Kuehl, Philip J / Hartke, Jim / Cihlar, Tomas / Porter, Danielle P

Science translational medicine

2022 Volume 14, Issue 633, Page(s) eabl8282

Abstract: Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as the first treatment for hospitalized COVID-19 patients. ... ...

Abstract	Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for non-hospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an IV administration of RDV at 10 mg/kg, an approximately 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed following inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with IV RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning approximately 8 hours post-infection. Moreover, the efficacy of inhaled RDV was similar to that of IV RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Alanine/analogs & derivatives ; Animals ; Antiviral Agents/pharmacokinetics ; Chlorocebus aethiops ; Humans ; Primates ; SARS-CoV-2 ; Viral Load ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2022-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abl8282
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Article ; Online: Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection.

Antiviral research

2022 Volume 203, Page(s) 105329

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has infected over 260 million people over the past 2 years. Remdesivir (RDV, VEKLURY®) is currently the only antiviral therapy fully approved by ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has infected over 260 million people over the past 2 years. Remdesivir (RDV, VEKLURY®) is currently the only antiviral therapy fully approved by the FDA for the treatment of COVID-19. The parent nucleoside of RDV, GS-441524, exhibits antiviral activity against numerous respiratory viruses including SARS-CoV-2, although at reduced in vitro potency compared to RDV in most assays. Here we find in both human alveolar and bronchial primary cells, GS-441524 is metabolized to the pharmacologically active GS-441524 triphosphate (TP) less efficiently than RDV, which correlates with a lower in vitro SARS-CoV-2 antiviral activity. In vivo, African green monkeys (AGM) orally dosed with GS-441524 yielded low plasma levels due to limited oral bioavailability of <10%. When GS-441524 was delivered via intravenous (IV) administration, although plasma concentrations of GS-441524 were significantly higher, lung TP levels were lower than observed from IV RDV. To determine the required systemic exposure of GS-441524 associated with in vivo antiviral efficacy, SARS-CoV-2 infected AGMs were treated with a once-daily IV dose of either 7.5 or 20 mg/kg GS-441524 or IV RDV for 5 days and compared to vehicle control. Despite the reduced lung TP formation compared to IV dosing of RDV, daily treatment with IV GS-441524 resulted in dose-dependent efficacy, with the 20 mg/kg GS-441524 treatment resulting in significant reductions of SARS-CoV-2 replication in the lower respiratory tract of infected animals. These findings demonstrate the in vivo SARS-CoV-2 antiviral efficacy of GS-441524 and support evaluation of its orally bioavailable prodrugs as potential therapies for COVID-19.
MeSH term(s)	Adenosine/analogs & derivatives ; Animals ; Antiviral Agents/therapeutic use ; Chlorocebus aethiops ; Humans ; Pandemics ; SARS-CoV-2 ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; GS-441524 (1BQK176DT6) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2022-05-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2022.105329
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Article ; Online: Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys.

Mackman, Richard L / Kalla, Rao V / Babusis, Darius / Pitts, Jared / Barrett, Kimberly T / Chun, Kwon / Du Pont, Venice / Rodriguez, Lauren / Moshiri, Jasmine / Xu, Yili / Lee, Michael / Lee, Gary / Bleier, Blake / Nguyen, Anh-Quan / O'Keefe, B Michael / Ambrosi, Andrea / Cook, Meredith / Yu, Joy / Dempah, Kassibla Elodie /

Bunyan, Elaine / Riola, Nicholas C / Lu, Xianghan / Liu, Renmeng / Davie, Ashley / Hsiang, Tien-Ying / Dearing, Justin / Vermillion, Meghan / Gale, Michael / Niedziela-Majka, Anita / Feng, Joy Y / Hedskog, Charlotte / Bilello, John P / Subramanian, Raju / Cihlar, Tomas

Journal of medicinal chemistry

2023 Volume 66, Issue 17, Page(s) 11701–11717

Abstract: ... ...

Abstract	Remdesivir
MeSH term(s)	Chlorocebus aethiops ; Humans ; Animals ; SARS-CoV-2 ; COVID-19 ; COVID-19 Drug Treatment ; Nucleosides ; Prodrugs/pharmacology ; Prodrugs/therapeutic use ; RNA, Viral ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Furans
Chemical Substances	GS-441524 (1BQK176DT6) ; Nucleosides ; Prodrugs ; RNA, Viral ; Antiviral Agents ; Furans
Language	English
Publishing date	2023-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c00750
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Article ; Online: The pUL37 tegument protein guides alpha-herpesvirus retrograde axonal transport to promote neuroinvasion.

Richards, Alexsia L / Sollars, Patricia J / Pitts, Jared D / Stults, Austin M / Heldwein, Ekaterina E / Pickard, Gary E / Smith, Gregory A

PLoS pathogens

2017 Volume 13, Issue 12, Page(s) e1006741

Abstract: A hallmark property of the neurotropic alpha-herpesvirinae is the dissemination of infection to sensory and autonomic ganglia of the peripheral nervous system following an initial exposure at mucosal surfaces. The peripheral ganglia serve as the latent ... ...

Abstract	A hallmark property of the neurotropic alpha-herpesvirinae is the dissemination of infection to sensory and autonomic ganglia of the peripheral nervous system following an initial exposure at mucosal surfaces. The peripheral ganglia serve as the latent virus reservoir and the source of recurrent infections such as cold sores (herpes simplex virus type I) and shingles (varicella zoster virus). However, the means by which these viruses routinely invade the nervous system is not fully understood. We report that an internal virion component, the pUL37 tegument protein, has a surface region that is an essential neuroinvasion effector. Mutation of this region rendered herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) incapable of spreading by retrograde axonal transport to peripheral ganglia both in culture and animals. By monitoring the axonal transport of individual viral particles by time-lapse fluorescence microscopy, the mutant viruses were determined to lack the characteristic sustained intracellular capsid motion along microtubules that normally traffics capsids to the neural soma. Consistent with the axonal transport deficit, the mutant viruses did not reach sites of latency in peripheral ganglia, and were avirulent. Despite this, viral propagation in peripheral tissues and in cultured epithelial cell lines remained robust. Selective elimination of retrograde delivery to the nervous system has long been sought after as a means to develop vaccines against these ubiquitous, and sometimes devastating viruses. In support of this potential, we find that HSV-1 and PRV mutated in the effector region of pUL37 evoked effective vaccination against subsequent nervous system challenges and encephalitic disease. These findings demonstrate that retrograde axonal transport of the herpesviruses occurs by a virus-directed mechanism that operates by coordinating opposing microtubule motors to favor sustained retrograde delivery of the virus to the peripheral ganglia. The ability to selectively eliminate the retrograde axonal transport mechanism from these viruses will be useful in trans-synaptic mapping studies of the mammalian nervous system, and affords a new vaccination paradigm for human and veterinary neurotropic herpesviruses.
MeSH term(s)	Amino Acid Sequence ; Animals ; Axonal Transport/genetics ; Axonal Transport/physiology ; Axons/virology ; Ganglia/virology ; Genes, Viral ; Herpesvirus 1, Human/genetics ; Herpesvirus 1, Human/pathogenicity ; Herpesvirus 1, Human/physiology ; Herpesvirus 1, Suid/genetics ; Herpesvirus 1, Suid/pathogenicity ; Herpesvirus 1, Suid/physiology ; Host-Pathogen Interactions/genetics ; Host-Pathogen Interactions/physiology ; Humans ; Male ; Mice ; Mice, Inbred DBA ; Models, Molecular ; Mutation ; Neurons/virology ; Rats ; Rats, Long-Evans ; Viral Structural Proteins/chemistry ; Viral Structural Proteins/genetics ; Viral Structural Proteins/physiology ; Viral Vaccines/genetics ; Virulence/genetics ; Virulence/physiology ; Virus Release/genetics ; Virus Release/physiology
Chemical Substances	UL37 protein, Human herpesvirus 1 ; Viral Structural Proteins ; Viral Vaccines
Language	English
Publishing date	2017-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1006741
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Article ; Online: Remdesivir and GS-441524 retain antiviral activity against Delta, Omicron, and other emergent SARS-CoV-2 variants

Pitts, Jared / Li, Jiani / Perry, Jason / Du Pont, Venice / Riola, Nicholas / Rodriguez, Lauren / Lu, Xianghan / Kurhade, Chaitanya / Xie, Xuping / Camus, Gregory / Manhas, Savrina / Martin, Ross / Shi, Pei-Yong / Cihlar, Tomas / Porter, Danielle Poulin / Mo, Hongmei / Maiorova, Evguenia S / Bilello, John P

bioRxiv

Abstract: Genetic variation of SARS-CoV-2 has resulted in the emergence and rapid spread of multiple variants throughout the pandemic, of which Omicron is currently the predominant variant circulating worldwide. SARS-CoV-2 variants of concern or interest (VOC/VOI) ...

Abstract	Genetic variation of SARS-CoV-2 has resulted in the emergence and rapid spread of multiple variants throughout the pandemic, of which Omicron is currently the predominant variant circulating worldwide. SARS-CoV-2 variants of concern or interest (VOC/VOI) have evidence of increased viral transmission, disease severity, or decreased effectiveness of vaccines and neutralizing antibodies. Remdesivir (RDV, VEKLURY<sup>®</sup>) is a nucleoside analog prodrug and the first FDA-approved antiviral treatment of COVID-19. Here we present a comprehensive antiviral activity assessment of RDV and its parent nucleoside, GS-441524, against 10 current and former SARS-CoV-2 VOC/VOI clinical isolates by nucleoprotein ELISA and plaque reduction assay. Delta and Omicron variants remained susceptible to RDV and GS-441524, with EC<sub>50</sub> values 0.31 to 0.62-fold of those observed against the ancestral WA1 isolate. All other tested variants exhibited EC<sub>50</sub> values ranging from 0.15 to 2.3-fold of the observed EC<sub>50</sub> values against WA1. Analysis of nearly 6 million publicly available variant isolate sequences confirmed that Nsp12, the RNA-dependent RNA polymerase (RdRp) target of RDV and GS-441524, is highly conserved across variants with only 2 prevalent changes (P323L and G671S). Using recombinant viruses, both RDV and GS-441524 retained potency against all viruses containing frequent variant substitutions or their combination. Taken together, these results highlight the conserved nature of SARS-CoV-2 Nsp12 and provide evidence of sustained SARS-CoV-2 antiviral activity of RDV and GS-441524 across the tested variants. The observed pan-variant activity of RDV supports its continued use for the treatment of COVID-19 regardless of the SARS-CoV-2 variant.
Keywords	covid19
Language	English
Publishing date	2022-02-10
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.02.09.479840
Database	COVID19

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