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Article ; Online: Calpain-2 mediates SARS-CoV-2 entry via regulating ACE2 levels.

Zeng, Qiru / Antia, Avan / Casorla-Perez, Luis Alberto / Puray-Chavez, Maritza / Kutluay, Sebla B / Ciorba, Matthew A / Ding, Siyuan

mBio

2024 Volume 15, Issue 3, Page(s) e0228723

Abstract: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show ... ...

Abstract	Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show excellent antiviral activities against SARS-CoV-2 by targeting the viral main protease (M Importance: Many efforts in small-molecule screens have been made to counter SARS-CoV-2 infection by targeting the viral main protease, the major element that processes viral proteins after translation. Here, we discovered that calpain inhibitors further block SARS-CoV-2 infection in a main protease-independent manner. We identified the host cysteine protease calpain-2 as an important positive regulator of the cell surface levels of SARS-CoV-2 cellular receptor ACE2 and, thus, a facilitator of viral infection. By either pharmacological inhibition or genetic knockout of calpain-2, the SARS-CoV-2 binding to host cells is blocked and viral infection is decreased. Our findings highlight a novel mechanism of ACE2 regulation, which presents a potential new therapeutic target. Since calpain inhibitors also potently interfere with the viral main protease, our data also provide a mechanistic understanding of the potential use of calpain inhibitors as dual inhibitors (entry and replication) in the clinical setting of COVID-19 diseases. Our findings bring mechanistic insights into the cellular process of SARS-CoV-2 entry and offer a novel explanation to the mechanism of activities of calpain inhibitors.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; Calpain/metabolism ; Calpain/pharmacology ; Angiotensin-Converting Enzyme 2/metabolism ; Spike Glycoprotein, Coronavirus/metabolism ; Antiviral Agents/pharmacology ; Virus Internalization
Chemical Substances	spike protein, SARS-CoV-2 ; Calpain (EC 3.4.22.-) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Spike Glycoprotein, Coronavirus ; Antiviral Agents
Language	English
Publishing date	2024-02-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.02287-23
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: SARS-CoV-2 Omicron BA.1 Variant Infection of Human Colon Epithelial Cells.

Antia, Avan / Alvarado, David M / Zeng, Qiru / Casorla-Perez, Luis A / Davis, Deanna L / Sonnek, Naomi M / Ciorba, Matthew A / Ding, Siyuan

Viruses

2024 Volume 16, Issue 4

Abstract: The Omicron variant of SARS-CoV-2, characterized by multiple subvariants including BA.1, XBB.1.5, EG.5, and JN.1, became the predominant strain in early 2022. Studies indicate that Omicron replicates less efficiently in lung tissue compared to the ... ...

Abstract	The Omicron variant of SARS-CoV-2, characterized by multiple subvariants including BA.1, XBB.1.5, EG.5, and JN.1, became the predominant strain in early 2022. Studies indicate that Omicron replicates less efficiently in lung tissue compared to the ancestral strain. However, the infectivity of Omicron in the gastrointestinal tract is not fully defined, despite the fact that 70% of COVID-19 patients experience digestive disease symptoms. Here, using primary human colonoids, we found that, regardless of individual variability, Omicron infects colon cells similarly or less effectively than the ancestral strain or the Delta variant. The variant induced limited type III interferon expression and showed no significant impact on epithelial integrity. Further experiments revealed inefficient cell-to-cell spread and spike protein cleavage in the Omicron spike protein, possibly contributing to its lower infectious particle levels. The findings highlight the variant-specific replication differences in human colonoids, providing insights into the enteric tropism of Omicron and its relevance to long COVID symptoms.
MeSH term(s)	Humans ; SARS-CoV-2/genetics ; SARS-CoV-2/physiology ; SARS-CoV-2/pathogenicity ; Colon/virology ; COVID-19/virology ; Epithelial Cells/virology ; Spike Glycoprotein, Coronavirus/metabolism ; Spike Glycoprotein, Coronavirus/genetics ; Virus Replication ; Interferon Lambda
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Interferon Lambda
Language	English
Publishing date	2024-04-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v16040634
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Calpain-2 mediates SARS-CoV-2 entry and represents a therapeutic target.

Zeng, Qiru / Antia, Avan / Puray-Chavez, Maritza / Kutluay, Sebla B / Ding, Siyuan

bioRxiv : the preprint server for biology

2022

Abstract	Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show excellent antiviral activities against SARS-CoV-2 by targeting the viral main protease (M
Language	English
Publishing date	2022-11-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.11.29.518418
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Rotavirus NSP1 Contributes to Intestinal Viral Replication, Pathogenesis, and Transmission.

Hou, Gaopeng / Zeng, Qiru / Matthijnssens, Jelle / Greenberg, Harry B / Ding, Siyuan

mBio

2021 Volume 12, Issue 6, Page(s) e0320821

Abstract: Rotavirus (RV)-encoded nonstructural protein 1 (NSP1), the product of gene segment 5, effectively antagonizes host interferon (IFN) signaling via multiple mechanisms. Recent studies with the newly established RV reverse genetics system indicate that NSP1 ...

Abstract	Rotavirus (RV)-encoded nonstructural protein 1 (NSP1), the product of gene segment 5, effectively antagonizes host interferon (IFN) signaling via multiple mechanisms. Recent studies with the newly established RV reverse genetics system indicate that NSP1 is not essential for the replication of the simian RV SA11 strain in cell culture. However, the role of NSP1 in RV infection
MeSH term(s)	Animals ; Humans ; Interferons/genetics ; Interferons/metabolism ; Intestines/metabolism ; Intestines/virology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Rotavirus/genetics ; Rotavirus/pathogenicity ; Rotavirus/physiology ; Rotavirus Infections/genetics ; Rotavirus Infections/metabolism ; Rotavirus Infections/virology ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism ; Virus Replication
Chemical Substances	STAT1 Transcription Factor ; Stat1 protein, mouse ; Viral Nonstructural Proteins ; Interferons (9008-11-1)
Language	English
Publishing date	2021-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.03208-21
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Calpain-2 mediates SARS-CoV-2 entry and represents a therapeutic target

Zeng, Qiru / Antia, Avan / Chavez, Maritza Puray / Kutluay, Sebla Bulent / Ding, Siyuan

bioRxiv

Abstract	Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show excellent antiviral activities against SARS-CoV-2 by targeting the viral main protease (Mpro), which plays an essential role in processing viral polyproteins. In this study, we found that calpain inhibitors potently inhibited the infection of a chimeric vesicular stomatitis virus (VSV) encoding the SARS-CoV-2 spike protein, but not Mpro. In contrast, calpain inhibitors did not exhibit antiviral activities towards the wild-type VSV with its native glycoprotein. Genetic knockout of calpain-2 by CRISPR/Cas9 conferred resistance of the host cells to the chimeric VSV-SARS-CoV-2 virus and a clinical isolate of wild-type SARS-CoV-2. Mechanistically, calpain-2 facilitates SARS-CoV-2 spike protein-mediated cell attachment by positively regulating the cell surface levels of ACE2. These results highlight an Mpro-independent pathway targeted by calpain inhibitors for efficient viral inhibition. We also identify calpain-2 as a novel host factor and a potential therapeutic target responsible for SARS-CoV-2 infection at the entry step.
Keywords	covid19
Language	English
Publishing date	2022-11-29
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.11.29.518418
Database	COVID19

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Article ; Online: SARS-CoV-2 Omicron BA.1 variant infection of human colon epithelial cells

Antia, Avan / Alvarado, David M / Zeng, Qiru / Davis, Deanna L / Ciorba, Matthew A / Ding, Siyuan

bioRxiv

Abstract: Omicron B.1.1.529 became the predominant SARS-CoV-2 variant in early 2022, causing a new wave of public anxiety. Compared to the ancestral strain, Omicron has 50 mutations, with over 30 mutations in the spike protein. These differences likely underlie ... ...

Abstract	Omicron B.1.1.529 became the predominant SARS-CoV-2 variant in early 2022, causing a new wave of public anxiety. Compared to the ancestral strain, Omicron has 50 mutations, with over 30 mutations in the spike protein. These differences likely underlie the changes in Omicron biology noted in other studies, including an attenuation in the lung parenchyma, compared to the ancestral SARS-CoV-2 strain and other variants, as well as a preference for endosomal entry, in place of the TMPRSS2-mediated membrane fusion pathway. This raises questions on Omicron tropism and infectivity in various target organ systems, including the gastrointestinal (GI) tract. Up to 70% of COVID-19 patients report GI symptoms, including nausea, vomiting, and diarrhea. Here, we show that in the context of donor intrinsic genetic heterogeneity, the SARS-CoV-2 Omicron variant infects human colonoids similarly, if not less effectively, than the ancestral WT (WA1) strain or the Delta variant. Additionally, we note a higher ratio of viral RNA to infectious virus titer, which may suggest that Omicron is potentially less infectious in the intestine. This study lays the foundation for further work defining mechanisms mediating intestinal infection and pathogenesis by Omicron.
Keywords	covid19
Language	English
Publishing date	2022-04-14
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.04.13.487939
Database	COVID19

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Article ; Online: CMPK2 is a host restriction factor that inhibits infection of multiple coronaviruses in a cell-intrinsic manner.

Zhu, Mingjun / Lv, Jiahuang / Wang, Wei / Guo, Rongli / Zhong, Chunyan / Antia, Avan / Zeng, Qiru / Li, Jizong / Liu, Qingtao / Zhou, Jinzhu / Zhu, Xuejiao / Fan, Baochao / Ding, Siyuan / Li, Bin

PLoS biology

2023 Volume 21, Issue 3, Page(s) e3002039

Abstract: Coronaviruses (CoVs) comprise a group of important human and animal pathogens. Despite extensive research in the past 3 years, the host innate immune defense mechanisms against CoVs remain incompletely understood, limiting the development of effective ... ...

Abstract	Coronaviruses (CoVs) comprise a group of important human and animal pathogens. Despite extensive research in the past 3 years, the host innate immune defense mechanisms against CoVs remain incompletely understood, limiting the development of effective antivirals and non-antibody-based therapeutics. Here, we performed an integrated transcriptomic analysis of porcine jejunal epithelial cells infected with porcine epidemic diarrhea virus (PEDV) and identified cytidine/uridine monophosphate kinase 2 (CMPK2) as a potential host restriction factor. CMPK2 exhibited modest antiviral activity against PEDV infection in multiple cell types. CMPK2 transcription was regulated by interferon-dependent and interferon regulatory factor 1 (IRF1)-dependent pathways post-PEDV infection. We demonstrated that 3'-deoxy-3',4'-didehydro-cytidine triphosphate (ddhCTP) catalysis by Viperin, another interferon-stimulated protein, was essential for CMPK2's antiviral activity. Both the classical catalytic domain and the newly identified antiviral key domain of CMPK2 played crucial roles in this process. Together, CMPK2, viperin, and ddhCTP suppressed the replication of several other CoVs of different genera through inhibition of the RNA-dependent RNA polymerase activities. Our results revealed a previously unknown function of CMPK2 as a restriction factor for CoVs, implying that CMPK2 might be an alternative target of interfering with the viral polymerase activity.
MeSH term(s)	Humans ; Animals ; Swine ; Coronavirus ; Interferons ; Coronavirus Infections ; Antiviral Agents/pharmacology ; Proteins/genetics ; Porcine epidemic diarrhea virus/genetics
Chemical Substances	Interferons (9008-11-1) ; Antiviral Agents ; Proteins
Language	English
Publishing date	2023-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3002039
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeting the Fusion Process of SARS-CoV-2 Infection by Small Molecule Inhibitors.

Park, Seung Bum / Irvin, Parker / Hu, Zongyi / Khan, Mohsin / Hu, Xin / Zeng, Qiru / Chen, Catherine / Xu, Miao / Leek, Madeleine / Zang, Ruochen / Case, James Brett / Zheng, Wei / Ding, Siyuan / Liang, T Jake

mBio

2022 Volume 13, Issue 1, Page(s) e0323821

Abstract: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a serious threat to global public health, underscoring the urgency of developing effective therapies. Therapeutics and, more ... ...

Abstract	Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a serious threat to global public health, underscoring the urgency of developing effective therapies. Therapeutics and, more specifically, direct-acting antiviral development are still very much in their infancy. Here, we report that two hepatitis C virus (HCV) fusion inhibitors identified in our previous study, dichlorcyclizine and fluoxazolevir, broadly block human coronavirus entry into various cell types. Both compounds were effective against various human-pathogenic CoVs in multiple assays based on vesicular stomatitis virus (VSV) pseudotyped with the spike protein and spike-mediated syncytium formation. The antiviral effects were confirmed in SARS-CoV-2 infection systems. These compounds were equally effective against recently emerged variants, including the delta variant. Cross-linking experiments and structural modeling suggest that the compounds bind to a hydrophobic pocket near the fusion peptide of S protein, consistent with their potential mechanism of action as fusion inhibitors. In summary, these fusion inhibitors have broad-spectrum antiviral activities and may be promising leads for treatment of SARS-CoV-2, its variants, and other pathogenic CoVs.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Antiviral Agents/pharmacology ; Spike Glycoprotein, Coronavirus/metabolism ; Hepatitis C, Chronic ; Virus Internalization
Chemical Substances	Antiviral Agents ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.03238-21
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes.

Zang, Ruochen / Gomez Castro, Maria Florencia / McCune, Broc T / Zeng, Qiru / Rothlauf, Paul W / Sonnek, Naomi M / Liu, Zhuoming / Brulois, Kevin F / Wang, Xin / Greenberg, Harry B / Diamond, Michael S / Ciorba, Matthew A / Whelan, Sean P J / Ding, Siyuan

Science immunology

2020 Volume 5, Issue 47

Abstract: Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report ... ...

Abstract	Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report productive infection of SARS-CoV-2 in ACE2
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Animals ; Betacoronavirus/physiology ; Cell Line ; Duodenum/cytology ; Enterocytes/pathology ; Enterocytes/virology ; Humans ; Membrane Proteins/metabolism ; Mice ; Organoids/virology ; Peptidyl-Dipeptidase A/metabolism ; Rotavirus/physiology ; SARS-CoV-2 ; Serine Endopeptidases/metabolism ; Vesiculovirus/genetics ; Virus Internalization
Chemical Substances	Membrane Proteins ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Ace2 protein, mouse (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-) ; TMPRSS4 protein, human (EC 3.4.21.-)
Keywords	covid19
Language	English
Publishing date	2020-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abc3582
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: JIB-04 Has Broad-Spectrum Antiviral Activity and Inhibits SARS-CoV-2 Replication and Coronavirus Pathogenesis.

Son, Juhee / Huang, Shimeng / Zeng, Qiru / Bricker, Traci L / Case, James Brett / Zhou, Jinzhu / Zang, Ruochen / Liu, Zhuoming / Chang, Xinjian / Darling, Tamarand L / Xu, Jian / Harastani, Houda H / Chen, Lu / Gomez Castro, Maria Florencia / Zhao, Yongxiang / Kohio, Hinissan P / Hou, Gaopeng / Fan, Baochao / Niu, Beibei /

Guo, Rongli / Rothlauf, Paul W / Bailey, Adam L / Wang, Xin / Shi, Pei-Yong / Martinez, Elisabeth D / Brody, Steven L / Whelan, Sean P J / Diamond, Michael S / Boon, Adrianus C M / Li, Bin / Ding, Siyuan

mBio

2022 Volume 13, Issue 1, Page(s) e0337721

Abstract: Pathogenic coronaviruses are a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified small-molecule inhibitors that potently block the replication of severe acute respiratory ... ...

Abstract	Pathogenic coronaviruses are a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified small-molecule inhibitors that potently block the replication of severe acute respiratory syndrome virus 2 (SARS-CoV-2). Among them, JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with a 50% effective concentration of 695 nM, with a specificity index of greater than 1,000. JIB-04 showed
MeSH term(s)	Chlorocebus aethiops ; Humans ; Animals ; Swine ; SARS-CoV-2 ; Antiviral Agents/pharmacology ; COVID-19/metabolism ; Virus Replication ; Vero Cells
Chemical Substances	Antiviral Agents ; JIB-04
Language	English
Publishing date	2022-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.03377-21
Database	MEDical Literature Analysis and Retrieval System OnLINE

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