Loxapine inhibits replication of hepatitis A virus in vitro and in vivo by targeting viral protein 2C

No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially life-threatening disease. Chemical screening of a small-compound library using nanoluciferase-expressing HAV identified loxapine succinate, a selectiv...

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Published inPLoS pathogens Vol. 20; no. 3; p. e1012091
Main Authors Matsuda, Mami, Hirai-Yuki, Asuka, Kotani, Osamu, Kataoka, Michiyo, Zheng, Xin, Yamane, Daisuke, Yokoyama, Masaru, Ishii, Koji, Muramatsu, Masamichi, Suzuki, Ryosuke
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 13.03.2024
Public Library of Science (PLoS)
Subjects
Analysis
Animals
Antiviral agents
Antiviral drugs
Biological response modifiers
Biology and life sciences
Care and treatment
Cytotoxicity
Dengue fever
Diagnosis
Dopamine
Dopamine D2 receptors
Dosage and administration
Drug development
Drugs
Food contamination & poisoning
Genomes
Genotype & phenotype
Health aspects
Hepatitis
Hepatitis A
Hepatitis A virus
Hepatitis A virus - genetics
Hepatitis A virus - metabolism
Hepatitis C
Infection
Internal ribosome entry site
Loxapine
Medical research
Medicine and health sciences
Medicine, Experimental
Methicillin
Mice
Molecular dynamics
Mutation
Phenothiazine
Physical Sciences
Protein 2C
Protein Biosynthesis
Proteins
Receptors
Replication
Research and Analysis Methods
Ribonucleic acid
RNA
RNA - metabolism
RNA polymerase
RNA, Viral - genetics
RNA, Viral - metabolism
Schizophrenia
Staphylococcus infections
Viral proteins
Viral Proteins - metabolism
Virus Replication - genetics
Viruses
Japan
United States > US
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Abstract No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially life-threatening disease. Chemical screening of a small-compound library using nanoluciferase-expressing HAV identified loxapine succinate, a selective dopamine receptor D2 antagonist, as a potent inhibitor of HAV propagation in vitro . Loxapine succinate did not inhibit viral entry nor internal ribosome entry site (IRES)-dependent translation, but exhibited strong inhibition of viral RNA replication. Blind passage of HAV in the presence of loxapine succinate resulted in the accumulation of viruses containing mutations in the 2C-encoding region, which contributed to resistance to loxapine succinate. Analysis of molecular dynamics simulations of the interaction between 2C and loxapine suggested that loxapine binds to the N-terminal region of 2C, and that resistant mutations impede these interactions. We further demonstrated that administration of loxapine succinate to HAV-infected Ifnar1 -/- mice (which lack the type I interferon receptor) results in decreases in the levels of fecal HAV RNA and of intrahepatic HAV RNA at an early stage of infection. These findings suggest that HAV protein 2C is a potential target for antivirals, and provide novel insights into the development of drugs for the treatment of hepatitis A.
AbstractList No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially life-threatening disease. Chemical screening of a small-compound library using nanoluciferase-expressing HAV identified loxapine succinate, a selective dopamine receptor D2 antagonist, as a potent inhibitor of HAV propagation in vitro. Loxapine succinate did not inhibit viral entry nor internal ribosome entry site (IRES)-dependent translation, but exhibited strong inhibition of viral RNA replication. Blind passage of HAV in the presence of loxapine succinate resulted in the accumulation of viruses containing mutations in the 2C-encoding region, which contributed to resistance to loxapine succinate. Analysis of molecular dynamics simulations of the interaction between 2C and loxapine suggested that loxapine binds to the N-terminal region of 2C, and that resistant mutations impede these interactions. We further demonstrated that administration of loxapine succinate to HAV-infected Ifnar1-/- mice (which lack the type I interferon receptor) results in decreases in the levels of fecal HAV RNA and of intrahepatic HAV RNA at an early stage of infection. These findings suggest that HAV protein 2C is a potential target for antivirals, and provide novel insights into the development of drugs for the treatment of hepatitis A.
No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially life-threatening disease. Chemical screening of a small-compound library using nanoluciferase-expressing HAV identified loxapine succinate, a selective dopamine receptor D2 antagonist, as a potent inhibitor of HAV propagation in vitro. Loxapine succinate did not inhibit viral entry nor internal ribosome entry site (IRES)-dependent translation, but exhibited strong inhibition of viral RNA replication. Blind passage of HAV in the presence of loxapine succinate resulted in the accumulation of viruses containing mutations in the 2C-encoding region, which contributed to resistance to loxapine succinate. Analysis of molecular dynamics simulations of the interaction between 2C and loxapine suggested that loxapine binds to the N-terminal region of 2C, and that resistant mutations impede these interactions. We further demonstrated that administration of loxapine succinate to HAV-infected Ifnar1.sup.-/- mice (which lack the type I interferon receptor) results in decreases in the levels of fecal HAV RNA and of intrahepatic HAV RNA at an early stage of infection. These findings suggest that HAV protein 2C is a potential target for antivirals, and provide novel insights into the development of drugs for the treatment of hepatitis A.
No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially life-threatening disease. Chemical screening of a small-compound library using nanoluciferase-expressing HAV identified loxapine succinate, a selective dopamine receptor D2 antagonist, as a potent inhibitor of HAV propagation in vitro . Loxapine succinate did not inhibit viral entry nor internal ribosome entry site (IRES)-dependent translation, but exhibited strong inhibition of viral RNA replication. Blind passage of HAV in the presence of loxapine succinate resulted in the accumulation of viruses containing mutations in the 2C-encoding region, which contributed to resistance to loxapine succinate. Analysis of molecular dynamics simulations of the interaction between 2C and loxapine suggested that loxapine binds to the N-terminal region of 2C, and that resistant mutations impede these interactions. We further demonstrated that administration of loxapine succinate to HAV-infected Ifnar1 -/- mice (which lack the type I interferon receptor) results in decreases in the levels of fecal HAV RNA and of intrahepatic HAV RNA at an early stage of infection. These findings suggest that HAV protein 2C is a potential target for antivirals, and provide novel insights into the development of drugs for the treatment of hepatitis A. Hepatitis A outbreaks have occurred world-wide, not only in developing countries but also in developed countries, resulting in 15,000–30,000 mortalities annually. However, no antiviral drugs currently are available for the treatment of hepatitis A virus (HAV) infection. Using a reporter-based recombinant HAV, a chemical library of pharmacologically active compounds was screened to identify drugs that specifically inhibit HAV propagation. We show here that loxapine succinate, a tricyclic antipsychotic medication that has been approved by the US FDA for the treatment of schizophrenia, is a potent inhibitor of HAV replication. The effect of loxapine on HAV appears to be independent of the dopamine D2 receptor (the target of the antipsychotic activity), instead corresponding to affinity for the HAV 2C protein, as demonstrated by molecular analysis of loxapine-resistant virus as well as in silico modeling. We further showed that administration of loxapine succinate to HAV-infected Ifnar1 -/- mice (which lack the type 1 interferon receptor) resulted in decreases in the levels of fecal HAV RNA and of intrahepatic HAV RNA at an early stage. Together, these results suggest a new target for the development of therapeutics for the treatment of HAV-infected patients.
No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially life-threatening disease. Chemical screening of a small-compound library using nanoluciferase-expressing HAV identified loxapine succinate, a selective dopamine receptor D2 antagonist, as a potent inhibitor of HAV propagation in vitro. Loxapine succinate did not inhibit viral entry nor internal ribosome entry site (IRES)-dependent translation, but exhibited strong inhibition of viral RNA replication. Blind passage of HAV in the presence of loxapine succinate resulted in the accumulation of viruses containing mutations in the 2C-encoding region, which contributed to resistance to loxapine succinate. Analysis of molecular dynamics simulations of the interaction between 2C and loxapine suggested that loxapine binds to the N-terminal region of 2C, and that resistant mutations impede these interactions. We further demonstrated that administration of loxapine succinate to HAV-infected Ifnar1-/- mice (which lack the type I interferon receptor) results in decreases in the levels of fecal HAV RNA and of intrahepatic HAV RNA at an early stage of infection. These findings suggest that HAV protein 2C is a potential target for antivirals, and provide novel insights into the development of drugs for the treatment of hepatitis A.No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially life-threatening disease. Chemical screening of a small-compound library using nanoluciferase-expressing HAV identified loxapine succinate, a selective dopamine receptor D2 antagonist, as a potent inhibitor of HAV propagation in vitro. Loxapine succinate did not inhibit viral entry nor internal ribosome entry site (IRES)-dependent translation, but exhibited strong inhibition of viral RNA replication. Blind passage of HAV in the presence of loxapine succinate resulted in the accumulation of viruses containing mutations in the 2C-encoding region, which contributed to resistance to loxapine succinate. Analysis of molecular dynamics simulations of the interaction between 2C and loxapine suggested that loxapine binds to the N-terminal region of 2C, and that resistant mutations impede these interactions. We further demonstrated that administration of loxapine succinate to HAV-infected Ifnar1-/- mice (which lack the type I interferon receptor) results in decreases in the levels of fecal HAV RNA and of intrahepatic HAV RNA at an early stage of infection. These findings suggest that HAV protein 2C is a potential target for antivirals, and provide novel insights into the development of drugs for the treatment of hepatitis A.
No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially life-threatening disease. Chemical screening of a small-compound library using nanoluciferase-expressing HAV identified loxapine succinate, a selective dopamine receptor D2 antagonist, as a potent inhibitor of HAV propagation in vitro . Loxapine succinate did not inhibit viral entry nor internal ribosome entry site (IRES)-dependent translation, but exhibited strong inhibition of viral RNA replication. Blind passage of HAV in the presence of loxapine succinate resulted in the accumulation of viruses containing mutations in the 2C-encoding region, which contributed to resistance to loxapine succinate. Analysis of molecular dynamics simulations of the interaction between 2C and loxapine suggested that loxapine binds to the N-terminal region of 2C, and that resistant mutations impede these interactions. We further demonstrated that administration of loxapine succinate to HAV-infected Ifnar1 -/- mice (which lack the type I interferon receptor) results in decreases in the levels of fecal HAV RNA and of intrahepatic HAV RNA at an early stage of infection. These findings suggest that HAV protein 2C is a potential target for antivirals, and provide novel insights into the development of drugs for the treatment of hepatitis A.
Audience Academic
Author Ishii, Koji
Yokoyama, Masaru
Muramatsu, Masamichi
Kataoka, Michiyo
Hirai-Yuki, Asuka
Kotani, Osamu
Suzuki, Ryosuke
Zheng, Xin
Yamane, Daisuke
Matsuda, Mami
AuthorAffiliation 7 Department of Infectious Disease Research, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
1 Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
2 Management Department of Biosafety, Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan
8 Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo, Japan
Rutgers University: Rutgers The State University of New Jersey, UNITED STATES
6 Department of Quality Assurance, Radiation Safety, and Information System, National Institute of Infectious Diseases, Tokyo, Japan
3 Pathogen Genomics Center, National Institute for Infectious Diseases, Tokyo, Japan
4 Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
5 Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
AuthorAffiliation_xml – name: 8 Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo, Japan
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– name: 5 Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
– name: Rutgers University: Rutgers The State University of New Jersey, UNITED STATES
– name: 3 Pathogen Genomics Center, National Institute for Infectious Diseases, Tokyo, Japan
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Copyright Copyright: © 2024 Matsuda et al. 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.
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2024 Matsuda 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.
2024 Matsuda et al 2024 Matsuda et al
2024 Matsuda 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.
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– notice: 2024 Matsuda 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: 2024 Matsuda et al 2024 Matsuda et al
– notice: 2024 Matsuda 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.
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License Copyright: © 2024 Matsuda et al. 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.
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The authors have declared that no competing interests exist.
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Snippet No antiviral drugs currently are available for treatment of infection by hepatitis A virus (HAV), a causative agent of acute hepatitis, a potentially...
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SubjectTerms Analysis
Animals
Antiviral agents
Antiviral drugs
Biological response modifiers
Biology and life sciences
Care and treatment
Cytotoxicity
Dengue fever
Diagnosis
Dopamine
Dopamine D2 receptors
Dosage and administration
Drug development
Drugs
Food contamination & poisoning
Genomes
Genotype & phenotype
Health aspects
Hepatitis
Hepatitis A
Hepatitis A virus
Hepatitis A virus - genetics
Hepatitis A virus - metabolism
Hepatitis C
Infection
Internal ribosome entry site
Loxapine
Medical research
Medicine and health sciences
Medicine, Experimental
Methicillin
Mice
Molecular dynamics
Mutation
Phenothiazine
Physical Sciences
Protein 2C
Protein Biosynthesis
Proteins
Receptors
Replication
Research and Analysis Methods
Ribonucleic acid
RNA
RNA - metabolism
RNA polymerase
RNA, Viral - genetics
RNA, Viral - metabolism
Schizophrenia
Staphylococcus infections
Viral proteins
Viral Proteins - metabolism
Virus Replication - genetics
Viruses
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Title Loxapine inhibits replication of hepatitis A virus in vitro and in vivo by targeting viral protein 2C
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http://dx.doi.org/10.1371/journal.ppat.1012091
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