antivirals – ETIDIoH

Human #Safety, Tolerability, and Pharmacokinetics of #Molnupiravir, a Novel Broad-Spectrum Oral #Antiviral Agent with Activity Against #SARS-CoV-2 (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2

Wendy P. Painter, Wayne Holman, Jim A. Bush, Firas Almazedi, Hamzah Malik, Nicola C. J. E. Eraut, Merribeth J. Morin, Laura J. Szewczyk, George R. Painter

DOI: 10.1128/AAC.02428-20

ABSTRACT

Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses.

Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.

EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.

Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.

This article is made available via the PMC Open Access Subset for unrestricted noncommercial re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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Keywords: SARS-CoV-2; COVID-19; Antivirals; Molnupiravir.

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The anti-influenza virus drug #favipiravir has little #effect on #replication of #SARS-CoV-2 in cultured cells (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

The anti-influenza virus drug favipiravir has little effect on replication of SARS-CoV-2 in cultured cells

Yuriko Tomita, Makoto Takeda, Shutoku Matsuyama

DOI: 10.1128/AAC.00020-21

ABSTRACT

Favipiravir (T-705, commercial name Avigan), a drug developed to treat influenza virus infection, has been used in some countries as an oral treatment for COVID-19; however, its clinical efficacy in this context is controversial.…

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Keywords: SARS-CoV-2; COVID-19; Antivirals; Favipiravir.

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#Intranasal fusion #inhibitory lipopeptide prevents direct-contact #SARS-CoV-2 #transmission in ferrets (Science, abstract)

[Source: Science, full page: (LINK). Abstract, edited.]

Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets

Rory D. de Vries1,*, Katharina S. Schmitz1,*, Francesca T. Bovier2,3,4,*, Camilla Predella2,5, Jonathan Khao6, Danny Noack1, Bart L. Haagmans1, Sander Herfst1, Kyle N. Stearns2,3,7, Jennifer Drew-Bear2,3, Sudipta Biswas8, Barry Rockx1, Gaël McGill6,9, N. Valerio Dorrello2, Samuel H. Gellman10, Christopher A. Alabi8,†, Rik L. de Swart1,†, Anne Moscona2,3,7,11,†, Matteo Porotto2,3,4,†

1 Department of Viroscience, Erasmus MC, Rotterdam, Netherlands. 2 Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA. 3 Center for Host–Pathogen Interaction, Columbia University Irving Medical Center, New York, NY, USA. 4 Department of Experimental Medicine, University of Campania “Luigi Vanvitelli,” Caserta, Italy. 5 Department of Biomedical Engineering, Politecnico di Milano, Milan, Italy. 6 Digizyme Inc., Brookline, MA, USA. 7 Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. 8 Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA. 9 Center for Molecular and Cellular Dynamics, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. 10 Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA. 11 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.

†Corresponding author. Email: caa238@cornell.edu (C.A.A.); r.deswart@erasmusmc.nl (R.L.d.S.); am939@cumc.columbia.edu (A.M.); mp3509@cumc.columbia.edu (M.P.)

* These authors contributed equally to this work.

Science 17 Feb 2021: eabf4896 | DOI: 10.1126/science.abf4896

Abstract

Containment of the COVID-19 pandemic requires reducing viral transmission. SARS-CoV-2 infection is initiated by membrane fusion between the viral and host cell membranes, mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection, and based on in vitro efficacy and in vivo biodistribution selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.

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Keywords: SARS-CoV-2; COVID-19; Antivirals (pre-clinical); Animal models.

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Development of cycling #probe based real-time #PCR methodology for #influenza A viruses possessing the #PA/I38T amino acid #substitution associated with reduced #baloxavir susceptibility (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 10 February 2021, 105036 | In Press, Journal Pre-proof

Development of cycling probe based real-time PCR methodology for influenza A viruses possessing the PA/I38T amino acid substitution associated with reduced baloxavir susceptibility

Hidekazu Osada a,b, Irina Chon a, Wint Wint Phyu a, Keita Wagatsuma a, Nobuo Nagata c, Takashi Kawashim a,d, Isamu Sato e, Tadashi Saito f, Naoki Kodo g, Hironori Masaki h, Norichika Asoh i, Yoshiko Tuchihashi i, Yutaka Shirahige j, Yasuhiko Ono k, Yasushi Shimada l, Hirotsune Hamabata m, Kousuke Saito a, Reiko Saito a,b

a Division of International Health (Public Health), Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; b Infectious Diseases Research Center of Niigata University in Myanmar, Yangon, Yangon Region, Myanmar; c Hiraoka-Kohen Pediatric Clinic, Sapporo, Hokkaido, Japan; d Kawashima Clinic, Shibukawa, Gunma, Japan; e Yoiko-no-Syounika Sato Pediatric Clinic, Niigata, Niigata, Japan; f Pediatric Department, Tako Central Hospital, Katori, Chiba, Japan; g Kodo Pediatric Clinic, Uji, Kyoto, Japan; h Masaki Respiratory Medicine Clinic, Nagasaki, Nagasaki, Japan; i Juzenkai Hospital, Nagasaki, Nagasaki, Japan; j Shirahige Clinic, Nagasaki, Nagasaki, Japan; k Ono Pediatric Clinic, Isahaya, Nagasaki, Japan; l Shimada Children′s Clinic, Kamiamakusa, Kumamoto, Japan; m Awase Daiichi Clinic, Okinawa, Okinawa, Japan

Received 15 May 2020, Revised 4 February 2021, Accepted 6 February 2021, Available online 10 February 2021.

DOI: https://doi.org/10.1016/j.antiviral.2021.105036

Highlights

We established cycling probe Real-time PCR systems to detect influenza A viruses with PA/I38T.
Pre-treatment prevalence of the PA/I38T mutant virus was 0.0% (0/129) for A(H1N1)pdm09 and 1.7% (4/229) for A/H3N2.
A(H3N2) PA/I38T viruses may be transmitted among humans in closed environments.

Abstract

Baloxavir marboxil has been used for influenza treatment since March 2018 in Japan. After baloxavir treatment, the most frequently detected substitution is Ile38Thr in polymerase acidic protein (PA/I38T), and this substitution reduces baloxavir susceptibility in influenza A viruses. To rapidly investigate the frequency of PA/I38T in influenza A(H1N1)pdm09 and A(H3N2) viruses in clinical samples, we established a rapid real-time system to detect single nucleotide polymorphisms in PA, using cycling probe real-time PCR. We designed two sets of probes that were labeled with either 6-carboxyfluorescein (FAM) or 6-carboxy-X-rhodamine (ROX) to identify PA/I38 (wild type strain) or PA/I38T, respectively. The established cycling probe real-time PCR system showed a dynamic linear range of 101 to 106 copies with high sensitivity in plasmid DNA controls. This real-time PCR system discriminated between PA/I38T and wild type viruses well. During the 2018/19 season, 377 influenza A-positive clinical samples were collected in Japan before antiviral treatment. Using our cycling probe real-time PCR system, we detected no (0/129, 0.0%) influenza A(H1N1)pdm09 viruses with PA/I38T substitutions and four A(H3N2) (4/229, 1.7%) with PA/I38T substitution prior to treatment. In addition, we found PA/I38T variant in siblings who did not received baloxavir treatment during an infection caused by A(H3N2) that afflicted the entire family. Although human-to-human transmission of PA/I38T variant may have occurred in a closed environment, the prevalence of this variant in influenza A viruses was still limited. Our cycling probe-PCR system is thus useful for antiviral surveillance of influenza A viruses possessing PA/I38T.

Keywords: influenza virus – baloxavir marboxil – PA/I38T substitution – cycling probe real-time PCR – antiviral susceptibility

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Keywords: Seasonal Influenza; H1N1pdm09; H3N2; Antivirals; Drugs Resistance; Baloxavir.

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In vivo structural characterization of the #SARS-CoV-2 RNA genome identifies host proteins vulnerable to repurposed drugs (Cell, abstract)

[Source: Cell, full page: (LINK). Abstract, edited.]

In vivo structural characterization of the SARS-CoV-2 RNA genome identifies host proteins vulnerable to repurposed drugs

Lei Sun, Pan Li, Xiaohui Ju, Jian Rao, Wenze Huang, Lili Ren, Shaojun Zhang, Tuanlin Xiong, Kui Xu, Xiaolin Zhou, Mingli Gong, Eric Miska, Qiang Ding, Jianwei Wang, Qiangfeng Cliff Zhang

Published: February 09, 2021 | DOI: https://doi.org/10.1016/j.cell.2021.02.008

Highlights

We generated in vivo structure maps and models of the SARS-CoV-2 RNA genome
Comparative analysis discovered conserved RNA structural features across coronaviruses
RNA structure-based prediction identified host proteins binding the SARS-CoV-2 genome
FDA-approved drugs targeting predicted host proteins potently suppress viral infection

Summary

SARS-CoV-2 is the cause of the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. Understanding of the RNA virus and its interactions with host proteins could improve therapeutic interventions for COVID-19. Using icSHAPE, we determined the structural landscape of SARS-CoV-2 RNA in infected human cells and from refolded RNAs, as well as of the regulatory untranslated regions of SARS-CoV-2 and six other coronaviruses. We validated several structural elements predicted in silico and discovered structural features that affect the translation and abundance of subgenomic viral RNAs in cells. The structural data informed a deep learning tool to predict 42 host proteins that bind to SARS-CoV-2 RNA. Strikingly, antisense oligonucleotides targeting the structural elements and FDA-approved drugs inhibiting the SARS-CoV-2 RNA binding proteins dramatically reduced SARS-CoV-2 infection in cells derived from human liver and lung tumors. Our findings thus shed light on coronavirus and reveal multiple candidate therapeutics for COVID-19 treatment.

Publication History – Accepted: February 2, 2021 – Received in revised form: October 1, 2020 – Received: July 10, 2020

Publication stage In Press Accepted Manuscript

Identification DOI: https://doi.org/10.1016/j.cell.2021.02.008

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Keywords: SARS-CoV-2; COVID-19; Antivirals.

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#SARS-CoV-2 #infection is effectively treated and prevented by #EIDD2801 (Nature, abstract)

[Source: Nature, full page: (LINK). Abstract, edited.]

SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801

Angela Wahl, Lisa E. Gralinski, […] J. Victor Garcia

Nature (2021)

Abstract

All known recently emerged human coronaviruses probably originated in bats1. Here we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat coronaviruses. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats harbour endogenous coronaviruses capable of direct transmission into humans. Further detailed analysis of pandemic SARS-CoV-2 in vivo infection of LoM human lung tissue showed predominant infection of human lung epithelial cells, including type II pneumocytes present in alveoli and ciliated airway cells. Acute SARS-CoV-2 infection was highly cytopathic and induced a robust and sustained type I interferon and inflammatory cytokine/chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for coronavirus infection. Our results show that therapeutic and prophylactic administration of EIDD-2801, an oral broad spectrum antiviral currently in phase II–III clinical trials, dramatically inhibited SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19.

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Keywords: SARS-CoV-2; COVID-19; Antivirals; Viral pathogenesis.

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AT-527, a double prodrug of a guanosine nucleotide analog, is a potent #inhibitor of #SARS-CoV-2 in vitro and a promising oral #antiviral for #treatment of #COVID19 (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

AT-527, a double prodrug of a guanosine nucleotide analog, is a potent inhibitor of SARS-CoV-2 in vitro and a promising oral antiviral for treatment of COVID-19

Steven S. Good, Jonna Westover, Kie Hoon Jung, Xiao-Jian Zhou, Adel Moussa, Paolo La Colla, Gabriella Collu, Bruno Canard, Jean-Pierre Sommadossi

DOI: 10.1128/AAC.02479-20

ABSTRACT

The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in HCV-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.47 μM, very similar to its EC90 against HCoV-229E, HCoV-OC43 and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 μM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 μM AT-511 (698 ± 15 and 236 ± 14 μM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of non-human primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.

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Keywords: SARS-CoV-2; COVID-19; Antivirals.

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Plitidepsin: a repurposed #drug for the #treatment of #COVID19 (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Plitidepsin: a repurposed drug for the treatment of COVID-19

Miguel Angel Martinez

DOI: 10.1128/AAC.00200-21

ABSTRACT

Finding antivirals to reduce coronavirus disease 2019 (COVID-19) morbidity and mortality has been challenging. Large randomized clinical trials that aimed to test four repurposed drugs, hydroxychloroquine, lopinavir-ritonavir, interferon beta-1a, and remdesivir, have shown that these compounds lacked impact on the COVID-19 course. Although the Phase III COVID-19 vaccine trial results are encouraging, the search for effective COVID-19 therapeutics should not stop. Recently, plitidepsin (aplidin) demonstrated highly effective preclinical activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its antiviral activity was 27.5-fold more potent than that of remdesivir (1). Plitidepsin, a repurposed drug developed for the treatment of multiple myeloma, targets the host translation cofactor eEF1A. Plitidepsin has shown efficacy in animal models and Phase I/II human trials. Although plitidepsin is administered intravenously and its toxicity profile remains to be fully characterized, this compound may be a promising alternative COVID-19 therapeutic.

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Keywords: SARS-CoV-2; COVID-19; Antivirals.

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#Genetic #Conservation of #SARS-CoV-2 #RNA #Replication Complex in Globally Circulating Isolates and Recently Emerged Variants from #Humans and #Minks Suggests Minimal Pre-Existing #Resistance to #Remdesivir (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 5 February 2021, 105033 | In Press, Journal Pre-proof | Research paper

Genetic Conservation of SARS-CoV-2 RNA Replication Complex in Globally Circulating Isolates and Recently Emerged Variants from Humans and Minks Suggests Minimal Pre-Existing Resistance to Remdesivir

Ross Martin, Jiani Li, Aiyippa Parvangada, Jason Perry, Tomas Cihlar, Hongmei Mo, Danielle Porter, Evguenia Svarovskaia, Gilead Sciences, 333 Lakeside Dr, Foster City, CA, USA

Received 19 December 2020, Revised 29 January 2021, Accepted 30 January 2021, Available online 5 February 2021.

DOI: https://doi.org/10.1016/j.antiviral.2021.105033

Highlights

Remdesivir (RDV) exhibits potent antiviral activity against SARS-CoV-2 and is currently the only drug approved for the treatment of COVID-19.
Little is known about the potential for pre-existing resistance to RDV and the global spread of SARS-CoV-2 and transmission between human and other species may lead to genetic diversification.
A large set of SARS-CoV-2 human clinical isolates (>90,000), including the recently emerged United Kingdom and South African SARS-CoV-2 variants, and mink isolates (>300) sequences were investigated for genetic changes in the RNA replication complex since the start of pandemic.
Low genetic diversity was observed in RNA replication complex in human clinical isolates and mink isolates.
Amino acid substitutions previously identified to cause reduced susceptibility to RDV in-vitro were observed at extremely low frequency (0.002%).
Other variants observed in clinical isolate sequences were modeled using Cryo-EM to evaluate proximity to RDV active site and potential impact on effectivity.

Abstract

Remdesivir (RDV) exhibits potent antiviral activity against SARS-CoV-2 and is currently the only drug approved for the treatment of COVID-19. However, little is currently known about the potential for pre-existing resistance to RDV and the possibility of SARS-CoV-2 genetic diversification that might impact RDV efficacy as the virus continue to spread globally. In this study, >90,000 SARS-CoV-2 sequences from globally circulating clinical isolates, including sequences from recently emerged United Kingdom and South Africa variants, and >300 from mink isolates were analyzed for genetic diversity in the RNA replication complex (nsp7, nsp8, nsp10, nsp12, nsp13, and nsp14) with a focus on the RNA-dependent RNA polymerase (nsp12), the molecular target of RDV. Overall, low genetic variation was observed with only 12 amino acid substitutions present in the entire RNA replication complex in ≥0.5% of analyzed sequences with the highest overall frequency (82.2%) observed for nsp12 P323L that consistently increased over time. Low sequence variation in the RNA replication complex was also observed among the mink isolates. Importantly, the coronavirus Nsp12 mutations previously selected in vitro in the presence of RDV were identified in only 2 isolates (0.002%) within all the analyzed sequences. In addition, among the sequence variants observed in ≥0.5% clinical isolates, including P323L, none were located near the established polymerase active site or sites critical for the RDV mechanism of inhibition. In summary, the low diversity and high genetic stability of the RNA replication complex observed over time and in the recently emerged SARS-CoV-2 variants suggests a minimal global risk of pre-existing SARS-CoV-2 resistance to RDV.

Keywords: SARS-CoV-2 – COVID-19 – nsp12 RdRp – Remdesivir – RDV – genetic diversity – resistance

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Keywords: SARS-CoV-2; COVID-19; Antivirals; Drugs resistance; Remdesivir.

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#Structure of the #SARS-CoV-2 #RdRp in the presence of #favipiravir-RTP (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP

Katerina Naydenova, Kyle W. Muir, Long-Fei Wu, Ziguo Zhang, Francesca Coscia, Mathew J. Peet, Pablo Castro-Hartmann, Pu Qian, Kasim Sader, Kyle Dent, Dari Kimanius, John D. Sutherland, Jan Löwe, David Barford, and Christopher J. Russo

PNAS February 16, 2021 118 (7) e2021946118; DOI: https://doi.org/10.1073/pnas.2021946118

Edited by Eva Nogales, University of California, Berkeley, CA, and approved January 11, 2021 (received for review October 20, 2020)

Significance

While the current COVID-19 pandemic continues, the US Food and Drug Administration (FDA) has approved only one drug against the virus—remdesivir. It is a nucleotide analogue inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase; favipiravir is another member of the same class. These nucleoside analogs were originally developed against other viral polymerases, and can be quickly repurposed against SARS-CoV-2 should they prove efficacious. We used cryoEM to visualize how favipiravir-RTP binds to the replicating SARS-CoV-2 polymerase and determine how it slows RNA replication. This structure explains the mechanism of action, and will help guide the design of more potent drugs targeting SARS-CoV-2.

Abstract

The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, nonproductive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp, which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.

COVID-19 – structural biology – cryoEM – T-705 – drug design

Footnotes

1 K.N., K.W.M., and L.-F.W. contributed equally to this work.

2 To whom correspondence may be addressed. Email: johns@mrc-lmb.cam.ac.uk, jyl@mrc-lmb.cam.ac.uk, dbarford@mrc-lmb.cam.ac.uk, and crusso@mrc-lmb.cam.ac.uk.

Author contributions: K.N., K.W.M., L.-F.W., J.D.S., J.L., D.B., and C.J.R. designed research; K.N., K.W.M., L.-F.W., Z.Z., F.C., M.J.P., P.C.-H., P.Q., K.S., and K.D. performed research; K.N., K.W.M., L.-F.W., Z.Z., and M.J.P. contributed new reagents/analytic tools; K.N., K.W.M., L.-F.W., Z.Z., F.C., K.D., D.K., J.D.S., J.L., D.B., and C.J.R. analyzed data; and K.N., K.W.M., L.-F.W., J.D.S., J.L., D.B., and C.J.R. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2021946118/-/DCSupplemental.

Data Availability. The electron scattering potential map is deposited in the Electron Microscopy Data Bank with accession code EMD-11692, and the atomic model is deposited in the PDB under accession code PDB ID 7AAP. The complete, unprocessed cryoEM dataset is deposited in the Electron Microscopy Public Image Archive under code EMPIAR-10517.

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Keywords: SARS-COV-2; COVID-19; Antivirals; Favipiravir.

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