SARS-CoV-2 variants with mutations at the S1/S2 cleavage site are generated in vitro during propagation in TMPRSS2-deficient cells

The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we ex...

Full description

Saved in:
Bibliographic Details
Published inPLoS pathogens Vol. 17; no. 1; p. e1009233
Main Authors Sasaki, Michihito, Uemura, Kentaro, Sato, Akihiko, Toba, Shinsuke, Sanaki, Takao, Maenaka, Katsumi, Hall, William W., Orba, Yasuko, Sawa, Hirofumi
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 21.01.2021
Public Library of Science (PLoS)
Subjects
ACE2
Amino Acid Sequence
Amino acids
Analysis
Angiotensin
Angiotensin-converting enzyme 2
Animals
Binding sites
Biology and life sciences
Caco-2 Cells
Cell Line
Chlorocebus aethiops
Cleavage
Cloning
Coronaviruses
COVID-19
Dilution
Gene mutations
Genetic aspects
Genomes
HEK293 Cells
Humans
Infections
Medicine and health sciences
Mutation
Nucleotides
Pandemics
Peptidyl-dipeptidase A
Progeny
Propagation
Proteins
Receptors
Research and Analysis Methods
S gene
SARS-CoV-2 - classification
SARS-CoV-2 - genetics
SARS-CoV-2 - growth & development
SARS-CoV-2 - physiology
Sequence Alignment
Serial Passage
Serine Endopeptidases - deficiency
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - genetics
Vero Cells
Viral diseases
Viral Tropism
Virions
Viruses
Japan
Online AccessGet full text

Cover

Abstract The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains.
AbstractList The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains.
The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains. SARS-CoV-2 uses its spike (S) protein to enter target cells. Unlike other similar coronaviruses, the nascent S protein has a polybasic cleavage motif and is cleaved by the host protease. We have identified SARS-CoV-2 variants with mutations at the cleavage motif of S protein (S gene mutants) which undergo inefficient proteolytic cleavage, generate smaller plaques, and infect fewer cell lines. Notably, S gene mutants emerged rapidly through SARS-CoV-2 propagation in Vero cells. Since Vero cells are commonly used for SARS-CoV-2 propagation, it is a very real possibility that researchers have performed experiments, screened antivirals, and developed vaccines using SARS-CoV-2 S gene mutants without realizing.
Introduction The World Health Organization has declared disease (COVID-19) due to infection with Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) as pandemic. The S protein forms a homotrimer on the virion surface and triggers viral entry into target cells via interactions between its receptor binding sites and the specific host receptors, angiotensin-converting enzyme 2 (ACE2) [4–6]. [...]the polybasic cleavage motif of the SARS-CoV-2 S protein has emerged as a feature of significant interest and importance. In order to characterize the properties of the S gene mutant viruses, we isolated four variant clones from progeny virus pools by limiting dilution and identified nucleotide mutations with a whole-genome analysis (S1 Table).
The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains.The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains.
Introduction The World Health Organization has declared disease (COVID-19) due to infection with Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) as pandemic. The S protein forms a homotrimer on the virion surface and triggers viral entry into target cells via interactions between its receptor binding sites and the specific host receptors, angiotensin-converting enzyme 2 (ACE2) [4–6]. [...]the polybasic cleavage motif of the SARS-CoV-2 S protein has emerged as a feature of significant interest and importance. In order to characterize the properties of the S gene mutant viruses, we isolated four variant clones from progeny virus pools by limiting dilution and identified nucleotide mutations with a whole-genome analysis (S1 Table).
The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains.
Audience Academic
Author Toba, Shinsuke
Sato, Akihiko
Orba, Yasuko
Uemura, Kentaro
Sanaki, Takao
Maenaka, Katsumi
Sawa, Hirofumi
Hall, William W.
Sasaki, Michihito
AuthorAffiliation 2 Shionogi & Co., Ltd., Osaka, Japan
1 Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
7 Global Virus Network, Baltimore, Maryland, United States of America
3 Laboratory of Biomolecular Science, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo, Japan
5 International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
6 National Virus Reference Laboratory, School of Medicine, University College of Dublin, Ireland
Johns Hopkins University Bloomberg School of Public Health, UNITED STATES
4 Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan
AuthorAffiliation_xml – name: 7 Global Virus Network, Baltimore, Maryland, United States of America
– name: Johns Hopkins University Bloomberg School of Public Health, UNITED STATES
– name: 2 Shionogi & Co., Ltd., Osaka, Japan
– name: 5 International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
– name: 1 Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
– name: 3 Laboratory of Biomolecular Science, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo, Japan
– name: 4 Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan
– name: 6 National Virus Reference Laboratory, School of Medicine, University College of Dublin, Ireland
Author_xml – sequence: 1
  givenname: Michihito
  orcidid: 0000-0003-1607-2175
  surname: Sasaki
  fullname: Sasaki, Michihito
– sequence: 2
  givenname: Kentaro
  surname: Uemura
  fullname: Uemura, Kentaro
– sequence: 3
  givenname: Akihiko
  surname: Sato
  fullname: Sato, Akihiko
– sequence: 4
  givenname: Shinsuke
  surname: Toba
  fullname: Toba, Shinsuke
– sequence: 5
  givenname: Takao
  orcidid: 0000-0001-8847-0071
  surname: Sanaki
  fullname: Sanaki, Takao
– sequence: 6
  givenname: Katsumi
  orcidid: 0000-0002-5459-521X
  surname: Maenaka
  fullname: Maenaka, Katsumi
– sequence: 7
  givenname: William W.
  surname: Hall
  fullname: Hall, William W.
– sequence: 8
  givenname: Yasuko
  orcidid: 0000-0001-9910-3912
  surname: Orba
  fullname: Orba, Yasuko
– sequence: 9
  givenname: Hirofumi
  orcidid: 0000-0003-2569-2755
  surname: Sawa
  fullname: Sawa, Hirofumi
BackLink https://www.ncbi.nlm.nih.gov/pubmed/33476327$$D View this record in MEDLINE/PubMed
BookMark eNqVk02P0zAQhiO0iP2Af4DAEhc4pGvHTpxyQKoqPiotH2oWrtbEcVJXaVxsp8CVX46zTdF2tUJCPtiyn3k982rmPDrpTKei6CnBE0I5uVyb3nbQTrZb8BOC8TSh9EF0RtKUxpxydnLrfBqdO7fGmBFKskfRKaWMZzThZ9HvYrYs4rn5FidoB1ZD5x36of0KbXoPXpvOIfDIrxQqyGWRINkq2EGjkNNeIbAKNapTFryqkO7QTntrUNVb3TVoa80WmhuV4e3645dlUSRxpWotteo8kqpt3ePoYQ2tU0_G_SL6-u7t9fxDfPX5_WI-u4olx6mPgfGSYU6gJCnGEjLFlUp4XfMyZ2mWpYArSEo6lTUBwlJZYYl5jsu0LgPK6UX0fK-7bY0To31OJGyKKWF5TgOx2BOVgbXYWr0B-0sY0OLmwthGgPU6WCBKXlacs-m0zhNGMgV1JSHNKprVJSasClpvxt_6cqMqGcq10B6JHr90eiUasxM8TynLcBB4OQpY871XzouNdoNh0CnTD3nnOOHThA95v7iD3l_dSDUQCtBdbcK_chAVsyzFOQk9Mbg0uYcKq1IbLUML1jrcHwW8OgoIjFc_fQO9c2JRLP-D_XTMPrtt4F_nDr0bgNd7QFrjnFW1kHrfsiFj3QqCxTAoBy_EMChiHJQQzO4EH_T_GfYHlfEXog
CitedBy_id crossref_primary_10_1371_journal_pone_0289198
crossref_primary_10_1016_j_xcrp_2023_101346
crossref_primary_10_1016_j_xinn_2022_100221
crossref_primary_10_3389_fimmu_2023_1197588
crossref_primary_10_1073_pnas_2304139120
crossref_primary_10_3389_fphar_2021_718484
crossref_primary_10_1128_aac_01315_22
crossref_primary_10_1128_spectrum_02692_24
crossref_primary_10_1016_j_bbrc_2022_04_071
crossref_primary_10_1016_j_cell_2021_08_017
crossref_primary_10_1128_spectrum_00716_22
crossref_primary_10_1371_journal_pone_0255622
crossref_primary_10_1080_07391102_2022_2160819
crossref_primary_10_1099_jgv_0_001584
crossref_primary_10_1016_j_isci_2021_103553
crossref_primary_10_1016_j_ebiom_2025_105662
crossref_primary_10_1021_acsinfecdis_3c00010
crossref_primary_10_1038_s41596_023_00897_6
crossref_primary_10_1128_mBio_01006_21
crossref_primary_10_1038_s41467_022_28654_5
crossref_primary_10_1126_scitranslmed_abq4064
crossref_primary_10_1515_dmpt_2022_0130
crossref_primary_10_1371_journal_ppat_1009500
crossref_primary_10_1002_jmv_27539
crossref_primary_10_3389_fimmu_2022_966236
crossref_primary_10_1007_s00018_021_03922_7
crossref_primary_10_1128_jvi_01532_22
crossref_primary_10_1073_pnas_2310421121
crossref_primary_10_1128_jvi_00474_22
crossref_primary_10_1007_s12015_021_10229_4
crossref_primary_10_1016_j_jgr_2022_07_003
crossref_primary_10_1128_JVI_01357_21
crossref_primary_10_1111_jfbc_14345
crossref_primary_10_1016_j_jbc_2021_100847
crossref_primary_10_1093_infdis_jiac083
crossref_primary_10_1038_s44298_024_00017_5
crossref_primary_10_1073_pnas_2111199119
crossref_primary_10_1016_j_ebiom_2023_104561
crossref_primary_10_1016_j_vaccine_2025_126951
crossref_primary_10_1021_acs_jmedchem_2c00117
crossref_primary_10_1038_s42003_025_07827_0
crossref_primary_10_1038_s41467_022_33911_8
crossref_primary_10_1128_mbio_03129_23
crossref_primary_10_1128_spectrum_01553_21
crossref_primary_10_1016_j_omtm_2022_01_015
crossref_primary_10_1016_j_coviro_2021_07_004
crossref_primary_10_1016_j_isci_2022_105314
crossref_primary_10_1016_j_vaccine_2021_08_081
crossref_primary_10_1016_j_coviro_2023_101303
crossref_primary_10_1038_s41467_021_26910_8
crossref_primary_10_1021_acs_jpcb_3c02910
crossref_primary_10_1016_j_ebiom_2022_104203
crossref_primary_10_1093_emph_eoac010
crossref_primary_10_2174_1566524021666211013121831
crossref_primary_10_1155_2024_1204825
crossref_primary_10_12688_f1000research_77421_3
crossref_primary_10_12688_f1000research_77421_2
crossref_primary_10_3389_fcimb_2022_869832
crossref_primary_10_12688_f1000research_77421_1
crossref_primary_10_2147_IDR_S391630
crossref_primary_10_1177_1721727X221095382
crossref_primary_10_18231_j_jmra_2023_003
crossref_primary_10_7554_eLife_89035
crossref_primary_10_1016_j_heliyon_2022_e12744
crossref_primary_10_1021_acs_biomac_4c00760
crossref_primary_10_3389_fcimb_2022_1003608
crossref_primary_10_1038_s41598_022_18367_6
crossref_primary_10_1371_journal_pone_0294262
crossref_primary_10_1073_pnas_2202012119
crossref_primary_10_7554_eLife_89035_3
crossref_primary_10_1016_j_isci_2021_103120
crossref_primary_10_1016_j_virs_2022_09_007
crossref_primary_10_1038_s41467_021_27881_6
crossref_primary_10_1111_tbed_14732
crossref_primary_10_1111_acel_14050
crossref_primary_10_1146_annurev_virology_093022_013037
crossref_primary_10_1016_j_scitotenv_2021_149834
crossref_primary_10_1038_s41467_021_23779_5
crossref_primary_10_15252_embj_2022111608
crossref_primary_10_1111_cts_13400
crossref_primary_10_1016_j_xcrm_2022_100849
crossref_primary_10_1021_acs_jproteome_3c00874
crossref_primary_10_1093_infdis_jiac276
crossref_primary_10_1016_j_virol_2022_08_003
crossref_primary_10_1371_journal_pone_0285861
crossref_primary_10_1016_j_virol_2022_01_014
crossref_primary_10_2147_IDR_S308176
crossref_primary_10_3389_fimmu_2021_796855
crossref_primary_10_1021_acs_jmedchem_2c01081
crossref_primary_10_1016_j_jhin_2022_01_001
crossref_primary_10_1038_s12276_024_01197_z
crossref_primary_10_1016_j_ebiom_2023_104950
crossref_primary_10_1186_s12985_022_01802_5
crossref_primary_10_3389_fvets_2023_1182165
crossref_primary_10_1126_sciadv_ade5085
crossref_primary_10_1016_j_micpath_2021_105108
crossref_primary_10_12688_f1000research_109701_1
crossref_primary_10_12688_f1000research_109701_2
crossref_primary_10_1038_s41589_022_01059_7
crossref_primary_10_1107_S2059798323000049
crossref_primary_10_1038_s41564_021_00908_w
crossref_primary_10_2174_1389450124666221014102927
crossref_primary_10_1038_s41467_024_44803_4
crossref_primary_10_1016_j_ymthe_2023_05_004
crossref_primary_10_1128_mBio_01415_21
crossref_primary_10_1007_s00705_021_05166_z
crossref_primary_10_1073_pnas_2105253118
crossref_primary_10_1021_acs_jpcb_4c03119
crossref_primary_10_1038_s41598_024_83633_8
crossref_primary_10_12688_f1000research_53137_1
crossref_primary_10_1016_j_bbrc_2021_09_015
crossref_primary_10_1007_s11356_022_22333_0
crossref_primary_10_1038_s41578_021_00305_z
crossref_primary_10_1111_1348_0421_12945
Cites_doi 10.1099/vir.0.81749-0
10.1128/JVI.00442-06
10.1016/j.virol.2017.12.015
10.1128/JVI.00074-08
10.1099/vir.0.071209-0
10.1016/j.cyto.2005.07.002
10.1073/pnas.2003138117
10.3390/v12060629
10.1016/j.virol.2017.02.014
10.1126/science.abb2507
10.1038/s41467-020-15562-9
10.1016/j.jmb.2020.04.009
10.1128/JVI.01294-10
10.1038/s41423-020-0400-4
10.1016/j.cell.2020.02.058
10.1016/j.isci.2020.101212
10.26508/lsa.202000786
10.1016/j.cell.2020.02.052
10.1016/j.bbadis.2020.165878
10.1146/annurev-virology-110615-042301
10.1128/JVI.01387-16
10.1128/JVI.00239-10
10.1038/s41591-020-0820-9
10.1073/pnas.0809524106
10.1073/pnas.0503203102
10.1073/pnas.2002589117
10.1080/22221751.2020.1756700
10.1038/s41422-020-0282-0
10.1128/AAC.00754-20
10.1016/0166-0934(88)90134-6
10.1016/j.jim.2012.12.010
10.1016/j.molcel.2020.04.022
10.1128/JVI.00676-08
10.1186/s13073-020-00763-0
10.3390/v4061011
10.1016/j.virol.2017.11.012
10.1128/JVI.00094-12
ContentType Journal Article
Copyright COPYRIGHT 2021 Public Library of Science
2021 Sasaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2021 Sasaki et al 2021 Sasaki et al
Copyright_xml – notice: COPYRIGHT 2021 Public Library of Science
– notice: 2021 Sasaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
– notice: 2021 Sasaki et al 2021 Sasaki et al
DBID AAYXX
CITATION
CGR
CUY
CVF
ECM
EIF
NPM
ISN
ISR
3V.
7QL
7U9
7X7
7XB
88E
8FE
8FH
8FI
8FJ
8FK
ABUWG
AEUYN
AFKRA
AZQEC
BBNVY
BENPR
BHPHI
C1K
CCPQU
COVID
DWQXO
FYUFA
GHDGH
GNUQQ
H94
HCIFZ
K9.
LK8
M0S
M1P
M7P
PHGZM
PHGZT
PIMPY
PJZUB
PKEHL
PPXIY
PQEST
PQGLB
PQQKQ
PQUKI
PRINS
7X8
5PM
DOA
DOI 10.1371/journal.ppat.1009233
DatabaseName CrossRef
Medline
MEDLINE
MEDLINE (Ovid)
MEDLINE
MEDLINE
PubMed
Gale In Context: Canada
Gale In Context: Science
ProQuest Central (Corporate)
Bacteriology Abstracts (Microbiology B)
Virology and AIDS Abstracts
Health & Medical Collection
ProQuest Central (purchase pre-March 2016)
Medical Database (Alumni Edition)
ProQuest SciTech Collection
ProQuest Natural Science Collection
ProQuest Hospital Collection
Hospital Premium Collection (Alumni Edition)
ProQuest Central (Alumni) (purchase pre-March 2016)
ProQuest Central (Alumni)
ProQuest One Sustainability
ProQuest Central UK/Ireland
ProQuest Central Essentials
Biological Science Database (Proquest)
ProQuest Central
Natural Science Collection
Environmental Sciences and Pollution Management
ProQuest One
Coronavirus Research Database
ProQuest Central
Health Research Premium Collection
Health Research Premium Collection (Alumni)
ProQuest Central Student
AIDS and Cancer Research Abstracts
SciTech Premium Collection
ProQuest Health & Medical Complete (Alumni)
Biological Sciences
ProQuest Health & Medical Collection
Medical Database ProQuest
Biological Science Database
ProQuest Central Premium
ProQuest One Academic
Publicly Available Content Database
ProQuest Health & Medical Research Collection
ProQuest One Academic Middle East (New)
ProQuest One Health & Nursing
ProQuest One Academic Eastern Edition (DO NOT USE)
ProQuest One Applied & Life Sciences
ProQuest One Academic
ProQuest One Academic UKI Edition
ProQuest Central China
MEDLINE - Academic
PubMed Central (Full Participant titles)
DOAJ Directory of Open Access Journals
DatabaseTitle CrossRef
MEDLINE
Medline Complete
MEDLINE with Full Text
PubMed
MEDLINE (Ovid)
Publicly Available Content Database
ProQuest Central Student
ProQuest One Academic Middle East (New)
ProQuest Central Essentials
ProQuest Health & Medical Complete (Alumni)
ProQuest Central (Alumni Edition)
SciTech Premium Collection
ProQuest One Community College
ProQuest One Health & Nursing
ProQuest Natural Science Collection
ProQuest Central China
Environmental Sciences and Pollution Management
ProQuest Central
ProQuest One Applied & Life Sciences
ProQuest One Sustainability
ProQuest Health & Medical Research Collection
Health Research Premium Collection
Health and Medicine Complete (Alumni Edition)
Natural Science Collection
ProQuest Central Korea
Bacteriology Abstracts (Microbiology B)
Health & Medical Research Collection
Biological Science Collection
AIDS and Cancer Research Abstracts
ProQuest Central (New)
ProQuest Medical Library (Alumni)
Virology and AIDS Abstracts
ProQuest Biological Science Collection
ProQuest One Academic Eastern Edition
Coronavirus Research Database
ProQuest Hospital Collection
Health Research Premium Collection (Alumni)
Biological Science Database
ProQuest SciTech Collection
ProQuest Hospital Collection (Alumni)
ProQuest Health & Medical Complete
ProQuest Medical Library
ProQuest One Academic UKI Edition
ProQuest One Academic
ProQuest One Academic (New)
ProQuest Central (Alumni)
MEDLINE - Academic
DatabaseTitleList CrossRef

Publicly Available Content Database
MEDLINE - Academic


MEDLINE
Database_xml – sequence: 1
  dbid: DOA
  name: DOAJ Directory of Open Access Journals
  url: https://www.doaj.org/
  sourceTypes: Open Website
– sequence: 2
  dbid: NPM
  name: PubMed
  url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
– sequence: 3
  dbid: EIF
  name: MEDLINE
  url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search
  sourceTypes: Index Database
– sequence: 4
  dbid: BENPR
  name: ProQuest Central
  url: https://www.proquest.com/central
  sourceTypes: Aggregation Database
DeliveryMethod fulltext_linktorsrc
Discipline Biology
DocumentTitleAlternate SARS-CoV-2 variants with mutations at the S1/S2 cleavage site
EISSN 1553-7374
ExternalDocumentID 2490314883
oai_doaj_org_article_b7bd77499f82416eafdca56d36fb014d
PMC7853460
A650814767
33476327
10_1371_journal_ppat_1009233
Genre Research Support, Non-U.S. Gov't
Journal Article
GeographicLocations Japan
GeographicLocations_xml – name: Japan
GrantInformation_xml – fundername: ;
  grantid: 16H06429
– fundername: ;
  grantid: 16H06431
– fundername: ;
  grantid: 16K21723
– fundername: ;
  grantid: 20wm0125008
– fundername: ;
  grantid: 20wm0225003
GroupedDBID ---
123
29O
2WC
53G
5VS
7X7
88E
8FE
8FH
8FI
8FJ
AAFWJ
AAUCC
AAWOE
AAYXX
ABDBF
ABUWG
ACGFO
ACIHN
ACPRK
ACUHS
ADBBV
AEAQA
AENEX
AEUYN
AFKRA
AFPKN
AFRAH
AHMBA
ALMA_UNASSIGNED_HOLDINGS
AOIJS
B0M
BAWUL
BBNVY
BCNDV
BENPR
BHPHI
BPHCQ
BVXVI
BWKFM
CCPQU
CITATION
CS3
DIK
DU5
E3Z
EAP
EAS
EBD
EMK
EMOBN
ESX
F5P
FPL
FYUFA
GROUPED_DOAJ
GX1
HCIFZ
HMCUK
HYE
IAO
IHR
INH
INR
ISN
ISR
ITC
KQ8
LK8
M1P
M48
M7P
MM.
O5R
O5S
OK1
OVT
P2P
PGMZT
PHGZM
PHGZT
PIMPY
PQQKQ
PROAC
PSQYO
PV9
QF4
QN7
RNS
RPM
RZL
SV3
TR2
TUS
UKHRP
WOW
~8M
3V.
ADRAZ
CGR
CUY
CVF
ECM
EIF
H13
IPNFZ
M~E
NPM
RIG
WOQ
PMFND
7QL
7U9
7XB
8FK
AZQEC
C1K
COVID
DWQXO
GNUQQ
H94
K9.
PJZUB
PKEHL
PPXIY
PQEST
PQGLB
PQUKI
PRINS
7X8
5PM
PUEGO
-
AAPBV
ABPTK
ADACO
BBAFP
ID FETCH-LOGICAL-c705t-a47b4071ab1500ca6e7ee27ff7b845665a0da2b39cf1a145cd0c0780b5fbe7e73
IEDL.DBID M48
ISSN 1553-7374
1553-7366
IngestDate Fri Nov 26 17:12:50 EST 2021
Wed Aug 27 01:03:45 EDT 2025
Thu Aug 21 18:14:56 EDT 2025
Tue Aug 05 10:18:25 EDT 2025
Fri Jul 25 10:27:56 EDT 2025
Tue Jun 17 21:00:36 EDT 2025
Tue Jun 10 20:46:39 EDT 2025
Fri Jun 27 04:03:43 EDT 2025
Fri Jun 27 04:11:19 EDT 2025
Wed Feb 19 02:28:59 EST 2025
Tue Jul 01 04:24:28 EDT 2025
Thu Apr 24 23:10:05 EDT 2025
IsDoiOpenAccess true
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Issue 1
Language English
License This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Creative Commons Attribution License
LinkModel DirectLink
MergedId FETCHMERGED-LOGICAL-c705t-a47b4071ab1500ca6e7ee27ff7b845665a0da2b39cf1a145cd0c0780b5fbe7e73
Notes new_version
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
I have read the journal's policy and the authors of this manuscript have the following competing interests: K.U., A.S., S.T., and T.S. are employees of Shionogi & Co., Ltd. Other authors have declared that no competing interests exist.
ORCID 0000-0003-2569-2755
0000-0002-5459-521X
0000-0001-9910-3912
0000-0003-1607-2175
0000-0001-8847-0071
OpenAccessLink http://journals.scholarsportal.info/openUrl.xqy?doi=10.1371/journal.ppat.1009233
PMID 33476327
PQID 2490314883
PQPubID 1436335
ParticipantIDs plos_journals_2490314883
doaj_primary_oai_doaj_org_article_b7bd77499f82416eafdca56d36fb014d
pubmedcentral_primary_oai_pubmedcentral_nih_gov_7853460
proquest_miscellaneous_2480279273
proquest_journals_2490314883
gale_infotracmisc_A650814767
gale_infotracacademiconefile_A650814767
gale_incontextgauss_ISR_A650814767
gale_incontextgauss_ISN_A650814767
pubmed_primary_33476327
crossref_citationtrail_10_1371_journal_ppat_1009233
crossref_primary_10_1371_journal_ppat_1009233
ProviderPackageCode CITATION
AAYXX
PublicationCentury 2000
PublicationDate 2021-01-21
PublicationDateYYYYMMDD 2021-01-21
PublicationDate_xml – month: 01
  year: 2021
  text: 2021-01-21
  day: 21
PublicationDecade 2020
PublicationPlace United States
PublicationPlace_xml – name: United States
– name: San Francisco
– name: San Francisco, CA USA
PublicationTitle PLoS pathogens
PublicationTitleAlternate PLoS Pathog
PublicationYear 2021
Publisher Public Library of Science
Public Library of Science (PLoS)
Publisher_xml – name: Public Library of Science
– name: Public Library of Science (PLoS)
References D Bestle (ppat.1009233.ref011) 2020; 3
H Chu (ppat.1009233.ref026) 2020
S Matsuyama (ppat.1009233.ref017) 2020; 117
M Kawase (ppat.1009233.ref031) 2012; 86
M Sasaki (ppat.1009233.ref043) 2015; 96
R Pauwels (ppat.1009233.ref046) 1988; 20
JK Millet (ppat.1009233.ref008) 2018; 517
Z Liu (ppat.1009233.ref022) 2020; 94
K Liao (ppat.1009233.ref027) 2013; 389
JA Jaimes (ppat.1009233.ref010) 2020; 432
Y Shirogane (ppat.1009233.ref037) 2008; 82
NS Ogando (ppat.1009233.ref021) 2020
Y Wada (ppat.1009233.ref036) 2017; 505
AD Davidson (ppat.1009233.ref023) 2020; 12
YT Wang (ppat.1009233.ref003) 2020
JA Jaimes (ppat.1009233.ref012) 2020; 23
W Tai (ppat.1009233.ref030) 2020; 17
CA de Haan (ppat.1009233.ref038) 2008; 82
VM Corman (ppat.1009233.ref044) 2020; 25
K Shirato (ppat.1009233.ref018) 2018; 517
S Bertram (ppat.1009233.ref028) 2010; 84
K Shirato (ppat.1009233.ref019) 2017; 91
D Wrapp (ppat.1009233.ref005) 2020; 367
KG Andersen (ppat.1009233.ref009) 2020; 26
M Hoffmann (ppat.1009233.ref033) 2020; 64
M Yamamoto (ppat.1009233.ref034) 2020; 12
M Hoffmann (ppat.1009233.ref015) 2020; 78
SY Lau (ppat.1009233.ref020) 2020; 9
AC Walls (ppat.1009233.ref004) 2020; 181
S Belouzard (ppat.1009233.ref040) 2009; 106
ppat.1009233.ref001
X Ren (ppat.1009233.ref025) 2006; 87
DJ Benton (ppat.1009233.ref006) 2020
J Shang (ppat.1009233.ref014) 2020; 117
AAT Naqvi (ppat.1009233.ref002) 2020; 1866
X Ou (ppat.1009233.ref016) 2020; 11
S Belouzard (ppat.1009233.ref042) 2012; 4
WB Klimstra (ppat.1009233.ref024) 2020
S Matsuyama (ppat.1009233.ref039) 2005; 102
L Overbergh (ppat.1009233.ref045) 2005; 31
M Hoffmann (ppat.1009233.ref013) 2020; 181
E Böttcher-Friebertshäuser (ppat.1009233.ref029) 2011; 85
M Wang (ppat.1009233.ref035) 2020; 30
Z Qiu (ppat.1009233.ref041) 2006; 80
Li F. Structure (ppat.1009233.ref007) 2016; 3
C Scavone (ppat.1009233.ref032) 2020
References_xml – volume: 87
  start-page: 1691
  issue: Pt 6
  year: 2006
  ident: ppat.1009233.ref025
  article-title: Analysis of ACE2 in polarized epithelial cells: surface expression and function as receptor for severe acute respiratory syndrome-associated coronavirus
  publication-title: J Gen Virol
  doi: 10.1099/vir.0.81749-0
– volume: 80
  start-page: 5768
  issue: 12
  year: 2006
  ident: ppat.1009233.ref041
  article-title: Endosomal proteolysis by cathepsins is necessary for murine coronavirus mouse hepatitis virus type 2 spike-mediated entry
  publication-title: J Virol
  doi: 10.1128/JVI.00442-06
– volume: 517
  start-page: 3
  year: 2018
  ident: ppat.1009233.ref008
  article-title: Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells
  publication-title: Virology
  doi: 10.1016/j.virol.2017.12.015
– volume: 82
  start-page: 6078
  issue: 12
  year: 2008
  ident: ppat.1009233.ref038
  article-title: Cleavage of group 1 coronavirus spike proteins: how furin cleavage is traded off against heparan sulfate binding upon cell culture adaptation
  publication-title: J Virol
  doi: 10.1128/JVI.00074-08
– volume: 96
  start-page: 440
  issue: Pt 2
  year: 2015
  ident: ppat.1009233.ref043
  article-title: Metagenomic analysis of the shrew enteric virome reveals novel viruses related to human stool-associated viruses
  publication-title: J Gen Virol
  doi: 10.1099/vir.0.071209-0
– volume: 31
  start-page: 454
  issue: 6
  year: 2005
  ident: ppat.1009233.ref045
  article-title: Validation of real-time RT-PCR assays for mRNA quantification in baboons
  publication-title: Cytokine
  doi: 10.1016/j.cyto.2005.07.002
– volume: 117
  start-page: 11727
  issue: 21
  year: 2020
  ident: ppat.1009233.ref014
  article-title: Cell entry mechanisms of SARS-CoV-2
  publication-title: Proc Natl Acad Sci U S A
  doi: 10.1073/pnas.2003138117
– volume: 12
  issue: 6
  year: 2020
  ident: ppat.1009233.ref034
  article-title: The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner
  publication-title: Viruses
  doi: 10.3390/v12060629
– volume: 505
  start-page: 102
  year: 2017
  ident: ppat.1009233.ref036
  article-title: Discovery of a novel antiviral agent targeting the nonstructural protein 4 (nsP4) of chikungunya virus
  publication-title: Virology
  doi: 10.1016/j.virol.2017.02.014
– volume: 367
  start-page: 1260
  issue: 6483
  year: 2020
  ident: ppat.1009233.ref005
  article-title: Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
  publication-title: Science
  doi: 10.1126/science.abb2507
– volume: 11
  start-page: 1620
  issue: 1
  year: 2020
  ident: ppat.1009233.ref016
  article-title: Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV
  publication-title: Nat Commun
  doi: 10.1038/s41467-020-15562-9
– volume: 432
  start-page: 3309
  issue: 10
  year: 2020
  ident: ppat.1009233.ref010
  article-title: Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop
  publication-title: J Mol Biol
  doi: 10.1016/j.jmb.2020.04.009
– volume: 85
  start-page: 1554
  issue: 4
  year: 2011
  ident: ppat.1009233.ref029
  article-title: Inhibition of influenza virus infection in human airway cell cultures by an antisense peptide-conjugated morpholino oligomer targeting the hemagglutinin-activating protease TMPRSS2
  publication-title: J Virol
  doi: 10.1128/JVI.01294-10
– volume: 17
  start-page: 613
  issue: 6
  year: 2020
  ident: ppat.1009233.ref030
  article-title: Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine
  publication-title: Cell Mol Immunol
  doi: 10.1038/s41423-020-0400-4
– volume: 181
  start-page: 281
  issue: 2
  year: 2020
  ident: ppat.1009233.ref004
  article-title: Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein
  publication-title: Cell
  doi: 10.1016/j.cell.2020.02.058
– volume: 23
  start-page: 101212
  issue: 6
  year: 2020
  ident: ppat.1009233.ref012
  article-title: Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1/S2 Site
  publication-title: iScience
  doi: 10.1016/j.isci.2020.101212
– volume: 3
  issue: 9
  year: 2020
  ident: ppat.1009233.ref011
  article-title: TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells
  publication-title: Life Sci Alliance
  doi: 10.26508/lsa.202000786
– year: 2020
  ident: ppat.1009233.ref026
  article-title: Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study
  publication-title: The Lancet Microbe
– volume: 181
  start-page: 271
  issue: 2
  year: 2020
  ident: ppat.1009233.ref013
  article-title: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
  publication-title: Cell
  doi: 10.1016/j.cell.2020.02.052
– volume: 1866
  start-page: 165878
  issue: 10
  year: 2020
  ident: ppat.1009233.ref002
  article-title: Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach
  publication-title: Biochim Biophys Acta Mol Basis Dis
  doi: 10.1016/j.bbadis.2020.165878
– volume: 3
  start-page: 237
  issue: 1
  year: 2016
  ident: ppat.1009233.ref007
  article-title: Function, and Evolution of Coronavirus Spike Proteins
  publication-title: Annu Rev Virol
  doi: 10.1146/annurev-virology-110615-042301
– volume: 25
  issue: 3
  year: 2020
  ident: ppat.1009233.ref044
  article-title: Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill.
– volume: 91
  issue: 1
  year: 2017
  ident: ppat.1009233.ref019
  article-title: Clinical Isolates of Human Coronavirus 229E Bypass the Endosome for Cell Entry
  publication-title: J Virol
  doi: 10.1128/JVI.01387-16
– volume: 84
  start-page: 10016
  issue: 19
  year: 2010
  ident: ppat.1009233.ref028
  article-title: TMPRSS2 and TMPRSS4 facilitate trypsin-independent spread of influenza virus in Caco-2 cells
  publication-title: J Virol
  doi: 10.1128/JVI.00239-10
– volume: 26
  start-page: 450
  issue: 4
  year: 2020
  ident: ppat.1009233.ref009
  article-title: The proximal origin of SARS-CoV-2
  publication-title: Nat Med
  doi: 10.1038/s41591-020-0820-9
– volume: 106
  start-page: 5871
  issue: 14
  year: 2009
  ident: ppat.1009233.ref040
  article-title: Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites
  publication-title: Proc Natl Acad Sci U S A
  doi: 10.1073/pnas.0809524106
– year: 2020
  ident: ppat.1009233.ref003
  article-title: Spiking Pandemic Potential: Structural and Immunological Aspects of SARS-CoV-2
  publication-title: Trends Microbiol
– year: 2020
  ident: ppat.1009233.ref032
  article-title: Current pharmacological treatments for COVID-19: What's next?
  publication-title: Br J Pharmacol
– volume: 102
  start-page: 12543
  issue: 35
  year: 2005
  ident: ppat.1009233.ref039
  article-title: Protease-mediated enhancement of severe acute respiratory syndrome coronavirus infection
  publication-title: Proc Natl Acad Sci U S A
  doi: 10.1073/pnas.0503203102
– volume: 117
  start-page: 7001
  issue: 13
  year: 2020
  ident: ppat.1009233.ref017
  article-title: Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells
  publication-title: Proc Natl Acad Sci U S A
  doi: 10.1073/pnas.2002589117
– volume: 9
  start-page: 837
  issue: 1
  year: 2020
  ident: ppat.1009233.ref020
  article-title: Attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction
  publication-title: Emerg Microbes Infect
  doi: 10.1080/22221751.2020.1756700
– volume: 30
  start-page: 269
  issue: 3
  year: 2020
  ident: ppat.1009233.ref035
  article-title: Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro
  publication-title: Cell Res
  doi: 10.1038/s41422-020-0282-0
– volume: 64
  issue: 6
  year: 2020
  ident: ppat.1009233.ref033
  article-title: Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19
  publication-title: Antimicrob Agents Chemother
  doi: 10.1128/AAC.00754-20
– volume: 20
  start-page: 309
  issue: 4
  year: 1988
  ident: ppat.1009233.ref046
  article-title: Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds
  publication-title: J Virol Methods
  doi: 10.1016/0166-0934(88)90134-6
– volume: 389
  start-page: 52
  issue: 1–2
  year: 2013
  ident: ppat.1009233.ref027
  article-title: Development of an enzymatic assay for the detection of neutralizing antibodies against therapeutic angiotensin-converting enzyme 2 (ACE2)
  publication-title: J Immunol Methods
  doi: 10.1016/j.jim.2012.12.010
– year: 2020
  ident: ppat.1009233.ref024
  article-title: SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected hospitalized COVID-19 patients
  publication-title: J Gen Virol
– year: 2020
  ident: ppat.1009233.ref006
  article-title: Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion
  publication-title: Nature
– ident: ppat.1009233.ref001
– volume: 78
  start-page: 779
  issue: 4
  year: 2020
  ident: ppat.1009233.ref015
  article-title: A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells
  publication-title: Mol Cell
  doi: 10.1016/j.molcel.2020.04.022
– volume: 82
  start-page: 8942
  issue: 17
  year: 2008
  ident: ppat.1009233.ref037
  article-title: Efficient multiplication of human metapneumovirus in Vero cells expressing the transmembrane serine protease TMPRSS2
  publication-title: J Virol
  doi: 10.1128/JVI.00676-08
– volume: 94
  issue: 17
  year: 2020
  ident: ppat.1009233.ref022
  article-title: Identification of Common Deletions in the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2
  publication-title: J Virol
– year: 2020
  ident: ppat.1009233.ref021
  article-title: SARS-coronavirus-2 replication in Vero E6 cells: replication kinetics, rapid adaptation and cytopathology
  publication-title: J Gen Virol
– volume: 12
  start-page: 68
  issue: 1
  year: 2020
  ident: ppat.1009233.ref023
  article-title: Characterisation of the transcriptome and proteome of SARS-CoV-2 reveals a cell passage induced in-frame deletion of the furin-like cleavage site from the spike glycoprotein
  publication-title: Genome Med
  doi: 10.1186/s13073-020-00763-0
– volume: 4
  start-page: 1011
  issue: 6
  year: 2012
  ident: ppat.1009233.ref042
  article-title: Mechanisms of coronavirus cell entry mediated by the viral spike protein
  publication-title: Viruses
  doi: 10.3390/v4061011
– volume: 517
  start-page: 9
  year: 2018
  ident: ppat.1009233.ref018
  article-title: Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry
  publication-title: Virology
  doi: 10.1016/j.virol.2017.11.012
– volume: 86
  start-page: 6537
  issue: 12
  year: 2012
  ident: ppat.1009233.ref031
  article-title: Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry
  publication-title: J Virol
  doi: 10.1128/JVI.00094-12
SSID ssj0041316
Score 2.6315947
Snippet The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic...
Introduction The World Health Organization has declared disease (COVID-19) due to infection with Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2)...
SourceID plos
doaj
pubmedcentral
proquest
gale
pubmed
crossref
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
Enrichment Source
StartPage e1009233
SubjectTerms ACE2
Amino Acid Sequence
Amino acids
Analysis
Angiotensin
Angiotensin-converting enzyme 2
Animals
Binding sites
Biology and life sciences
Caco-2 Cells
Cell Line
Chlorocebus aethiops
Cleavage
Cloning
Coronaviruses
COVID-19
Dilution
Gene mutations
Genetic aspects
Genomes
HEK293 Cells
Humans
Infections
Medicine and health sciences
Mutation
Nucleotides
Pandemics
Peptidyl-dipeptidase A
Progeny
Propagation
Proteins
Receptors
Research and Analysis Methods
S gene
SARS-CoV-2 - classification
SARS-CoV-2 - genetics
SARS-CoV-2 - growth & development
SARS-CoV-2 - physiology
Sequence Alignment
Serial Passage
Serine Endopeptidases - deficiency
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - genetics
Vero Cells
Viral diseases
Viral Tropism
Virions
Viruses
SummonAdditionalLinks – databaseName: DOAJ Directory of Open Access Journals
  dbid: DOA
  link: http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwrV3da9swEBcjMNjL2HezZUMbgz1psS1bsh-zstINWkbcjr4ZfXaBzg6xE9hr__Le2Y6pR0df9pq7yNHd-fRTdPodIR-5TrV3XDFnrWGxhVdRi8hALHtrVGi89njf-eRUHJ_H3y-Si1utvrAmrKMH7gw311JbgChZ5lNYbIRTOEYiLBdeA7y3mH1hzdtvprocDJm5bXqKTXGY5EL0l-a4DOe9jz6v1wrpowNAOHy0KLXc_UOGnqyvqvou-Pl3FeWtZenoCXnc40m66ObxlDxw5TPysOsw-ec5uc4Xy5wdVj9ZRHewLcaqF4r_vdLf2-4QvqaqoYACaR7O84jCIGoHOYbiqTJVG0cvW2JqAKZ0VdLdqtlUtLvbSOHHQjpqR0HZ2cmPZZ5HzDpkpYCfS_FUoH5Bzo--nh0es77tAjMySBqmYqlxm6c0gMXAKOGkc5H0XuoU4JZIVGBVpHlmfKjCODE2MAA0Ap14DaqSvySTsirdAaEmS4UDb0s8QM3SBOQ2dV5ksVGZ1cmU8L3dC9NzkmNrjKuiPWiTsDfpzFigt4reW1PChm-tO06Oe_S_oEsHXWTUbj-AOCv6OCvui7Mp-YABUSBnRolFOZdqW9fFt_y0WCDKDWMp5D-VliOlT72Sr2CyRvUXIcBkyMU10pyNNOHNNyPxAQbnfs51AVtp7EaQpjDl2T5g7xa_H8Q4KBbala7aok4aIKekBJ1XXXwPduMcnsojeK4cRf7IsGNJufrVUpZLQIWxCF7_D0-8IY8iLCwKQhaFMzJpNlv3FpBho9-1SeAGqTFjKg
  priority: 102
  providerName: Directory of Open Access Journals
– databaseName: Health & Medical Collection
  dbid: 7X7
  link: http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwhV1Lj9MwELagCIkL4r2FBRmExCk0iRM7OaGyYrUg7Qo1u6i3yM9upSUpTVuJK7-cmcQNBC1wzUwcP8bON_b4G0JeM5UpZ5kMrDE6SAxMRcVjDbbsjJaRdsrhfefTM35ykXyap3O_4db4sMr9mtgu1KbWuEc-ATcBmdazjL1bfQswaxServoUGjfJLaQuQ6sW897hgvW5TX2KqXECwTj3V-eYiCZ-pN6uVhJJpEPAOWzwa2oZ_Pt1erS6qpvrQOifsZS__ZyO75G7HlXSaWcG98kNWz0gt7s8k98fkh_FdFYER_WXIKY7cI4x9oXiDiz9uu2O4hsqNxSwIC2iSRFTKETuYKWh2Hoq15YuWnpqgKd0WdHdcrOuaXfDkUJlYVFqS0HZ-ennWVHEgbHITQHVpXg20DwiF8cfzo9OAp98IdAiTDeBTIRCZ08qgIyhltwKa2PhnFAZgC6eytDIWLFcu0hGSapNqAFuhCp1ClQFe0xGVV3ZA0J1nnELYy7wGDXPUpCbzDqeJ1rmRqVjwvb9XmrPTI4JMq7K9rhNgIfSdWOJo1X60RqToH9r1TFz_Ef_PQ5pr4u82u2Der0o_TQtlVAGAHGeuwygDbcSLTblhnGnwJk0Y_IKDaJE5owKQ3MWcts05cfirJwi1o0SwcVflWYDpTdeydXQWC39dQjoMmTkGmgeDjRh_uuB-ACNc9_mpvw1U-DNvcFeL37Zi7FQDLerbL1FnSxEZkkBOk86--77jTH4Kovhu2Jg-YOOHUqq5WVLXC4AGyY8fPrvaj0jd2IMHAqjII4OyWiz3trngPw26kU7vX8CGN9ZxA
  priority: 102
  providerName: ProQuest
Title SARS-CoV-2 variants with mutations at the S1/S2 cleavage site are generated in vitro during propagation in TMPRSS2-deficient cells
URI https://www.ncbi.nlm.nih.gov/pubmed/33476327
https://www.proquest.com/docview/2490314883
https://www.proquest.com/docview/2480279273
https://pubmed.ncbi.nlm.nih.gov/PMC7853460
https://doaj.org/article/b7bd77499f82416eafdca56d36fb014d
http://dx.doi.org/10.1371/journal.ppat.1009233
Volume 17
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwhV3db9MwELe2TqC9ID63QqkMQuIpI99OHhDqpk0DqdXUrGhvkT9LpZKUpq3YK385d_moFtSK19zZis939u989h0hHzwRCaM9bmmlpOUrMEURuhJ02SjJHWmEwffOw1F4PfG_3QV3B6Sp2VoLsNjp2mE9qclyfvb71_0XMPjPZdUG5jSNzhYLjgmhbcAs3iE5gr2JYU2Dob-NK8CK7YT1A7p9LY_JY8_zweyw0MyDvapM6b9duDuLeV7sQqX_Xq58sFtdPSVPaphJB5VePCMHOntOHlWFJ-9fkD_JYJxYF_l3y6Ub8JbxMgzFI1n6c13F5gvKVxTAIU2cT4lLoRO-gaWHYrCZ8qWm0zJfNeBVOsvoZrZa5rR68kjhZ2GVKntB2u3wZpwkrqU0JquA36UYLCheksnV5e3FtVVXY7Aks4OVxX0m0PvjAjCkLXmomdYuM4aJCFBYGHBbcVd4sTQOd_xAKlsC_rBFYASwMu8V6WR5pk8JlXEUalAChnHVOAqAriJtwtiXPFYi6BKvkXsq61TlWDFjnpbxNwYuSyXGFCcurSeuS6xtq0WVquM__Oc4pVteTLRdfsiX07S221QwoQAhx7GJQJ9CzVGFg1B5oRHgXaoueY8KkWIqjQzv6kz5uijSr8koHSD4dUCT2F6mcYvpY81kchis5PX7CBAZpuhqcfZanLAgyBb5FJWzGXORgoeNRQqiCIbcaxR2N_ndloyd4v27TOdr5IlsTDXJgOek0u-t3Bpr6RLW0vyWYNuUbPajzGTOACz6of16b59vyLGLl4hsx3KdHumslmv9FlDgSvTJIbtjfXJ0fjm6GffLs5R-aex_AdnqYP8
linkProvider Scholars Portal
linkToHtml http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwtV1Lb9QwELZKEYIL4t2FAgaBOJkmcWInB4RKoWrpQ2izRXsLfqWsVJJls1vUKz-I38hMkg0EFTj1mpk4yXg88008niHkGdexzh1XzFlrWGhhKWoRGNDl3Brlm1zneN754FDsHIXvx9F4hfxYnoXBtMqlTawNtS0N_iPfgDABK63HMX89_cqwaxTuri5baDRqsefOvkHIVr3afQvz-zwItt-NtnZY21WAGelFc6ZCqTGKURqwkGeUcNK5QOa51DGgCREpz6pA88TkvvLDyFjPgB_1dJRrYJUcxr1ELoPj9TDYk-MuwAN_ULdaxVY8THIh2qN6XPobrWa8nE4VFq32AFfxniusOwZ0fmF1elJW54HeP3M3f3OG2zfI9RbF0s1G7W6SFVfcIleavpZnt8n3dHOYsq3yIwvoKQTjmGtD8Y8v_bJotv4rquYUsCdN_Y00oDCIOgXLRlHaVM0cPa7LYQMcppOCnk7ms5I2JyopvCwYwXoUpI0OPgzTNGDWYS0MeF2KexHVHXJ0IdNyl6wWZeHWCDVJLBzomMRt2ySOgG5jl4skNCqxOhoQvpR7ZtpK6NiQ4ySrt_ckRESNGDOcraydrQFh3V3TphLIf_jf4JR2vFjHu75Qzo6z1ixkWmoLADxJ8higlHAKV0gkLBe5huDVDshTVIgMK3UUmAp0rBZVle2mh9kmYms_lEL-lWnYY3rRMuUlfKxR7fELEBlWAOtxrvc4wd6YHnkNlXP5zVX2a2XCnUuFPZ_8pCPjoJjeV7hygTyxh5UsJfDca_S7kxvn8FQewHNlT_N7gu1TisnnulC6BCwaCu_-v1_rMbm6MzrYz_Z3D_cekGsBJi15Pgv8dbI6ny3cQ0Cdc_2oXuqUfLpo2_ITEMmXVQ
linkToPdf http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwtV1Lb9NAEF6VVCAuiHcLBRYE4mRie22vfUAofamlNKriFvVm9hkqFTvESVCv_Cx-HTN-BIwKnHr1jNf27OzMN97ZGUJeMhlLa5hwjNbKCTQsRRn5CnTZaiU8ZaXF886Hw2jvJHh_Gp6ukB_tWRhMq2xtYmWodaHwH3kfwgSstB7HrG-btIij7d13k68OdpDCnda2nUatIgfm4huEb-Xb_W2Y61e-v7tzvLXnNB0GHMXdcOaIgEuMaIQEXOQqERlujM-t5TIGZBGFwtXClyxR1hNeECrtKvCprgytBFbOYNxrZJXjGD2yurkzPBq1fgC8Q9V4FRvzOJxFUXNwj3Gv3-jJm8lEYAlrF1AW6zjGqn_A0kv0JudFeRkE_jOT8zfXuHub3GowLR3USniHrJj8Lrled7m8uEe-p4NR6mwVHx2fLiA0x8wbiv9_6Zd5nQhQUjGjgERp6vVTn8IgYgF2jqK8qZgaOq6KYwM4pmc5XZzNpgWtz1dSeFkwidUoSDs-PBqlqe9og5Ux4HUp7kyU98nJlUzMA9LLi9ysEaqSODKgcRw3cZM4BLqOjY2SQIlEy3CdsFbumWrqomN7jvOs2uzjEB_VYsxwtrJmttaJs7xrUtcF-Q__Jk7pkherelcXiuk4a4xEJrnUAMeTxMYArCIjcL2EkWaRlRDK6nXyAhUiw7odOa6AsZiXZbafDrMBIm0v4BH_K9Oow_S6YbIFfKwSzWEMEBnWA-twbnQ4wfqoDnkNlbP95jL7tU7hzlZhLyc_X5JxUEz2y00xR57YxbqWHHge1vq9lBtj8FTmw3N5R_M7gu1S8rPPVdl0Dsg0iNxH_36tZ-QG2JXsw_7w4DG56WMGk-s5vrdBerPp3DwBCDqTT5u1TsmnqzYvPwEKHpzw
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=SARS-CoV-2+variants+with+mutations+at+the+S1%2FS2+cleavage+site+are+generated+in+vitro+during+propagation+in+TMPRSS2-deficient+cells&rft.jtitle=PLoS+pathogens&rft.au=Sasaki%2C+Michihito&rft.au=Uemura%2C+Kentaro&rft.au=Sato%2C+Akihiko&rft.au=Toba%2C+Shinsuke&rft.date=2021-01-21&rft.eissn=1553-7374&rft.volume=17&rft.issue=1&rft.spage=e1009233&rft_id=info:doi/10.1371%2Fjournal.ppat.1009233&rft_id=info%3Apmid%2F33476327&rft.externalDocID=33476327
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1553-7374&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1553-7374&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1553-7374&client=summon