Analgesics
Antiandrogens
Azvudine
Bromhexine
Budesonide
Colchicine
Conv. Plasma
Curcumin
Famotidine
Favipiravir
Fluvoxamine
Hydroxychlor..
Ivermectin
Lifestyle
Melatonin
Metformin
Minerals
Molnupiravir
Monoclonals
Naso/orophar..
Nigella Sativa
Nitazoxanide
Paxlovid
Quercetin
Remdesivir
Thermotherapy
Vitamins
More

Other
Feedback
Home
Top
Abstract
All molnupiravir studies
Meta analysis
 
Feedback
Home
next
study
previous
study
c19early.org COVID-19 treatment researchMolnupiravirMolnupiravir (more..)
Melatonin Meta
Metformin Meta
Azvudine Meta
Bromhexine Meta Molnupiravir Meta
Budesonide Meta
Colchicine Meta
Conv. Plasma Meta Nigella Sativa Meta
Curcumin Meta Nitazoxanide Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

All Studies   All Outcomes    Recent:   

β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells

Zhou et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247
May 2021  
  Post
  Facebook
Share
  Source   PDF   All Studies   Meta AnalysisMeta
In Vitro study showing that NHC (initial metabolite of molnupiravir) has high antiviral activity against SARS-CoV-2, but also shows host mutational activity in an animal cell culture assay. Authors note the concern that mutations in host DNA could contribute to the development of cancer, or cause birth defects either in a developing fetus or through incorporation into sperm precursor cells. Response from Merck:1.
Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer2-10. Multiple analyses have identified variants potentially created by molnupiravir11-14.
Zhou et al., 7 May 2021, peer-reviewed, 10 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperMolnupiravirAll
Abstract: The Journal of Infectious Diseases Brief Report β-d-N4-hydroxycytidine Inhibits SARSCoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells Shuntai Zhou,1, Collin S. Hill,1 Sanjay Sarkar,2 Longping V. Tse,3 Blaide M. D. Woodburn,1,4 Raymond F. Schinazi,5 Timothy P. Sheahan,3 Ralph S. Baric,3,6 Mark T. Heise,2,6 and Ronald Swanstrom1,7 Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral replication. β-d-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) is >100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host. Keywords. molnupiravir; mutagenicity; NHC; SARS-CoV-2. Emerging RNA viruses arising from highly heterogeneous pools of precursor strains are responsible for most recent epidemic and pandemic disease outbreaks in the late 20th and early 21st century. Broad direct-acting antiviral agents represent the most specific way of treating a viral infection, although these are often specific to a group of closely related viruses. Besides remdesivir, which blocks the replication of several coronaviruses, limited therapeutic options are available for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections [1]. β-d-N4-hydroxycytidine (NHC, or to designate Received 18 February 2021; editorial decision 1 May 2021; accepted 4 May 2021; published online May 7, 2021. Correspondence: Ronald Swanstrom, PhD, Room 22-006, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599 (risunc@med.unc. edu). The Journal of Infectious Diseases®  2021;224:415–9 © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. DOI: 10.1093/infdis/jiab247 METHODS We measured SARS-CoV-2 antiviral activity in the presence of a panel of compounds (rNHC, RBV, and FAV) using the A549-hACE2 cell model [9, 10]. Sequence analysis to detect the mutation load was done using the previously published multiplex Primer ID approach to sequence several regions of the BRIEF REPORT • jid 2021:224 (1 August) • 415 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 2Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 4Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA, 5Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA, 6Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North..
{ 'indexed': {'date-parts': [[2024, 5, 14]], 'date-time': '2024-05-14T09:48:25Z', 'timestamp': 1715680105947}, 'reference-count': 14, 'publisher': 'Oxford University Press (OUP)', 'issue': '3', 'license': [ { 'start': { 'date-parts': [[2021, 5, 7]], 'date-time': '2021-05-07T00:00:00Z', 'timestamp': 1620345600000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model'}], 'funder': [ { 'DOI': '10.13039/100000002', 'name': 'National Institutes of Health', 'doi-asserted-by': 'publisher', 'award': ['P30 CA16068', 'P30 AI50410', 'R01 AI140970', 'R01 AI141327', 'P30 AI050409']}, {'name': 'Antiviral Drug Discovery and Development Center', 'award': ['U19 AI142759']}, { 'DOI': '10.13039/100011072', 'name': 'UNC Center for AIDS Research', 'doi-asserted-by': 'publisher'}, { 'DOI': '10.13039/100008615', 'name': 'UNC Lineberger Comprehensive Cancer Center', 'doi-asserted-by': 'publisher'}, {'name': 'Emory Center for AIDS'}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'published-print': {'date-parts': [[2021, 8, 2]]}, 'abstract': '<jats:title>Abstract</jats:title><jats:p>Mutagenic ribonucleosides can act as broad-based ' 'antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and ' 'concentrate in genomes of RNA viruses during viral replication. β-d-N4-hydroxycytidine (NHC, ' 'initial metabolite of molnupiravir) is &amp;gt;100-fold more active than ribavirin or ' 'favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with ' 'antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also ' 'displays host mutational activity in an animal cell culture assay, consistent with RNA and ' 'DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results ' 'indicate highly active mutagenic ribonucleosides may hold risk for the host.</jats:p>', 'DOI': '10.1093/infdis/jiab247', 'type': 'journal-article', 'created': {'date-parts': [[2021, 5, 5]], 'date-time': '2021-05-05T13:25:20Z', 'timestamp': 1620221120000}, 'page': '415-419', 'source': 'Crossref', 'is-referenced-by-count': 219, 'title': 'β-<scp>d</scp>-<i>N</i>4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is ' 'Also Mutagenic To Mammalian Cells', 'prefix': '10.1093', 'volume': '224', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-8353-386X', 'authenticated-orcid': False, 'given': 'Shuntai', 'family': 'Zhou', 'sequence': 'first', 'affiliation': [ { 'name': 'Lineberger Comprehensive Cancer Center, University of North ' 'Carolina at Chapel Hill, Chapel Hill, North Carolina, USA'}]}, { 'given': 'Collin S', 'family': 'Hill', 'sequence': 'additional', 'affiliation': [ { 'name': 'Lineberger Comprehensive Cancer Center, University of North ' 'Carolina at Chapel Hill, Chapel Hill, North Carolina, USA'}]}, { 'given': 'Sanjay', 'family': 'Sarkar', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Genetics, University of North Carolina at Chapel ' 'Hill, Chapel Hill, North Carolina, USA'}]}, { 'given': 'Longping V', 'family': 'Tse', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Epidemiology, University of North Carolina at ' 'Chapel Hill, Chapel Hill, North Carolina, USA'}]}, { 'given': 'Blaide M D', 'family': 'Woodburn', 'sequence': 'additional', 'affiliation': [ { 'name': 'Lineberger Comprehensive Cancer Center, University of North ' 'Carolina at Chapel Hill, Chapel Hill, North Carolina, USA'}, { 'name': 'Department of Pharmacology, University of North Carolina at ' 'Chapel Hill, Chapel Hill, North Carolina, USA'}]}, { 'given': 'Raymond F', 'family': 'Schinazi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Biochemical Pharmacology, Department of ' 'Pediatrics, Emory University School of Medicine and Children’s ' 'Healthcare of Atlanta, Atlanta, Georgia, USA'}]}, { 'given': 'Timothy P', 'family': 'Sheahan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Epidemiology, University of North Carolina at ' 'Chapel Hill, Chapel Hill, North Carolina, USA'}]}, { 'given': 'Ralph S', 'family': 'Baric', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Epidemiology, University of North Carolina at ' 'Chapel Hill, Chapel Hill, North Carolina, USA'}, { 'name': 'Department of Microbiology and Immunology, University of North ' 'Carolina at Chapel Hill, Chapel Hill, North Carolina, USA'}]}, { 'given': 'Mark T', 'family': 'Heise', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Genetics, University of North Carolina at Chapel ' 'Hill, Chapel Hill, North Carolina, USA'}, { 'name': 'Department of Microbiology and Immunology, University of North ' 'Carolina at Chapel Hill, Chapel Hill, North Carolina, USA'}]}, { 'given': 'Ronald', 'family': 'Swanstrom', 'sequence': 'additional', 'affiliation': [ { 'name': 'Lineberger Comprehensive Cancer Center, University of North ' 'Carolina at Chapel Hill, Chapel Hill, North Carolina, USA'}, { 'name': 'Department of Biochemistry and Biophysics, University of North ' 'Carolina at Chapel Hill, Chapel Hill, North Carolina, USA'}]}], 'member': '286', 'published-online': {'date-parts': [[2021, 5, 7]]}, 'reference': [ { 'key': '2021080216301988800_CIT0001', 'article-title': 'Remdesivir in coronavirus disease 2019 (COVID-19) treatment: a review ' 'of evidence', 'author': 'Lin', 'journal-title': 'Infection'}, { 'key': '2021080216301988800_CIT0002', 'doi-asserted-by': 'crossref', 'first-page': 'eabb5883', 'DOI': '10.1126/scitranslmed.abb5883', 'article-title': 'An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in ' 'human airway epithelial cell cultures and multiple coronaviruses in ' 'mice', 'volume': '12', 'author': 'Sheahan', 'year': '2020', 'journal-title': 'Sci Transl Med'}, { 'key': '2021080216301988800_CIT0003', 'doi-asserted-by': 'crossref', 'first-page': 'e01348', 'DOI': '10.1128/JVI.01348-19', 'article-title': 'Small-molecule antiviral β-d-N4-hydroxycytidine inhibits a ' 'proofreading-intact coronavirus with a high genetic barrier to ' 'resistance', 'volume': '93', 'author': 'Agostini', 'year': '2019', 'journal-title': 'J Virol'}, { 'key': '2021080216301988800_CIT0004', 'doi-asserted-by': 'crossref', 'first-page': '451', 'DOI': '10.1038/s41586-021-03312-w', 'article-title': 'SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801', 'volume': '591', 'author': 'Wahl', 'year': '2021', 'journal-title': 'Nature'}, { 'key': '2021080216301988800_CIT0005', 'doi-asserted-by': 'crossref', 'DOI': '10.1128/AAC.02428-20', 'article-title': 'Human Safety, tolerability, and pharmacokinetics of molnupiravir, a ' 'novel broad-spectrum oral antiviral agent with activity against ' 'SARS-CoV-2', 'author': 'Painter', 'year': '2021', 'journal-title': 'Antimicrob Agents Chemother'}, { 'key': '2021080216301988800_CIT0006', 'article-title': 'A review on favipiravir: the properties, function, and usefulness to ' 'treat COVID-19', 'author': 'Hashemian', 'journal-title': 'Expert Rev Anti Infect Ther'}, { 'key': '2021080216301988800_CIT0007', 'doi-asserted-by': 'crossref', 'first-page': '6895', 'DOI': '10.1073/pnas.111085598', 'article-title': 'RNA virus error catastrophe: direct molecular test by using ribavirin', 'volume': '98', 'author': 'Crotty', 'year': '2001', 'journal-title': 'Proc Natl Acad Sci U S A'}, { 'key': '2021080216301988800_CIT0008', 'doi-asserted-by': 'crossref', 'first-page': '55', 'DOI': '10.1007/978-1-61779-421-6_4', 'article-title': 'Mammalian cell HPRT gene mutation assay: test methods', 'volume': '817', 'author': 'Johnson', 'year': '2012', 'journal-title': 'Methods Mol Biol'}, { 'key': '2021080216301988800_CIT0009', 'doi-asserted-by': 'crossref', 'first-page': '1464', 'DOI': '10.1126/science.abe8499', 'article-title': 'SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and ' 'transmission in vivo', 'volume': '370', 'author': 'Hou', 'year': '2020', 'journal-title': 'Science'}, { 'key': '2021080216301988800_CIT0010', 'doi-asserted-by': 'crossref', 'first-page': '429', 'DOI': '10.1016/j.cell.2020.05.042', 'article-title': 'SARS-CoV-2 reverse genetics reveals a variable infection gradient in ' 'the respiratory tract', 'volume': '182', 'author': 'Hou', 'year': '2020', 'journal-title': 'Cell'}, { 'key': '2021080216301988800_CIT0011', 'doi-asserted-by': 'crossref', 'first-page': 'e01652', 'DOI': '10.1128/AAC.01652-20', 'article-title': 'Repurposing nucleoside analogs for human coronaviruses', 'volume': '65', 'author': 'Zandi', 'year': '2020', 'journal-title': 'Antimicrob Agents Chemother'}, { 'key': '2021080216301988800_CIT0012', 'first-page': '739', 'article-title': 'Biosynthesis of nucleotides.', 'volume-title': 'Biochemistry', 'author': 'Stryer', 'year': '1995', 'edition': '4'}, { 'key': '2021080216301988800_CIT0013', 'doi-asserted-by': 'crossref', 'first-page': '99', 'DOI': '10.1186/s13059-016-0963-7', 'article-title': 'A comprehensive survey of the mutagenic impact of common cancer ' 'cytotoxics', 'volume': '17', 'author': 'Szikriszt', 'year': '2016', 'journal-title': 'Genome Biol'}, { 'key': '2021080216301988800_CIT0014', 'doi-asserted-by': 'crossref', 'first-page': '91', 'DOI': '10.1016/j.ijid.2020.03.017', 'article-title': 'Prevalence of comorbidities and its effects in patients infected with ' 'SARS-CoV-2: a systematic review and meta-analysis', 'volume': '94', 'author': 'Yang', 'year': '2020', 'journal-title': 'Int J Infect Dis'}], 'container-title': 'The Journal of Infectious Diseases', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'http://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiab247/38530589/jiab247.pdf', 'content-type': 'application/pdf', 'content-version': 'am', 'intended-application': 'syndication'}, { 'URL': 'http://academic.oup.com/jid/article-pdf/224/3/415/39541894/jiab247.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'syndication'}, { 'URL': 'http://academic.oup.com/jid/article-pdf/224/3/415/39541894/jiab247.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 12, 26]], 'date-time': '2022-12-26T11:28:44Z', 'timestamp': 1672054124000}, 'score': 1, 'resource': {'primary': {'URL': 'https://academic.oup.com/jid/article/224/3/415/6272009'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2021, 5, 7]]}, 'references-count': 14, 'journal-issue': { 'issue': '3', 'published-online': {'date-parts': [[2021, 5, 7]]}, 'published-print': {'date-parts': [[2021, 8, 2]]}}, 'URL': 'http://dx.doi.org/10.1093/infdis/jiab247', 'relation': {}, 'ISSN': ['0022-1899', '1537-6613'], 'subject': [], 'published-other': {'date-parts': [[2021, 8, 1]]}, 'published': {'date-parts': [[2021, 5, 7]]}}
Loading..
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop   
Submit