Soluble Coxsackievirus B3 3C Protease Inhibitor Prevents Cardiomyopathy in an Experimental Chronic Myocarditis Murine Model
•Re-established the chronic CVB3 myocarditis animal model for drug administration.•Produced water-soluble 3CPI by chemically modifying the water-insoluble 3CPI.•3CPI inhibited virus replication in various organs, myocardial damage, and reduced mortality.•Soluble 3CPI may be beneficial in the treatme...
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| Veröffentlicht in: | Virus research 2015-03, Vol.199, p.1-8 |
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| creator | Lim, Byung-Kwan Yun, Soo-Hyeon Ju, Eun-Seon Kim, Bo-Kyoung Lee, You-Jung Yoo, Dong-Kyeom Kim, Young-Chul Jeon, Eun-Seok |
| description | •Re-established the chronic CVB3 myocarditis animal model for drug administration.•Produced water-soluble 3CPI by chemically modifying the water-insoluble 3CPI.•3CPI inhibited virus replication in various organs, myocardial damage, and reduced mortality.•Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.
Coxsackievirus B3 (CVB3) is a common cause of myocarditis and dilated cardiomyopathy. CVB3 3C protease (3CP) cleaves the viral polyprotein during replication. We tested whether a water soluble 3CP inhibitor (3CPI) had antiviral effects in a chronic myocarditis model.
Chronic myocarditis was established using DBA/2 strain mice. Starting on post-infection (p.i) day 3, CVB3-infected mice (n=41) were treated with 3CPI by daily intraperitoneal (i.p.) injection at a concentration of 50μM (1.7mg/kg/day) per day for 3 consecutive days. Additional mice (n=49) were injected with PBS as a control.
The 5-week survival rate was significantly higher with 3CPI treatment (82.3% versus 47.9%; P |
| doi_str_mv | 10.1016/j.virusres.2014.11.030 |
| format | Article |
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Coxsackievirus B3 (CVB3) is a common cause of myocarditis and dilated cardiomyopathy. CVB3 3C protease (3CP) cleaves the viral polyprotein during replication. We tested whether a water soluble 3CP inhibitor (3CPI) had antiviral effects in a chronic myocarditis model.
Chronic myocarditis was established using DBA/2 strain mice. Starting on post-infection (p.i) day 3, CVB3-infected mice (n=41) were treated with 3CPI by daily intraperitoneal (i.p.) injection at a concentration of 50μM (1.7mg/kg/day) per day for 3 consecutive days. Additional mice (n=49) were injected with PBS as a control.
The 5-week survival rate was significantly higher with 3CPI treatment (82.3% versus 47.9%; P<0.05). Organ virus titers at day 3 and 7 and myocardial damage were significantly lower in 3CPI-treated mice. Echocardiography at day 31 indicated strong protection of heart function by 3CPI (FS, 51.2±1.5 versus 26.1±1.5%; P<0.001). Hemodynamic measurements indicated that 3CPI treatment markedly reduced CVB3-induced LV dysfunction on day 31 (dP/dTmax, 5302±352 versus 4103±408mmHg/s, P<0.05; dP/dTmin, −3798±212 versus −2814±206mmHg/s, P<0.01).
Water soluble 3CPI was delivered through i.p. injection after CVB3 infection. This agent preserved heart function and decreased organ viral titers and myocardial damage. Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.</description><identifier>ISSN: 0168-1702</identifier><identifier>EISSN: 1872-7492</identifier><identifier>DOI: 10.1016/j.virusres.2014.11.030</identifier><identifier>PMID: 25485472</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>3C Viral Proteases ; Animals ; Antiviral agent ; Antiviral Agents - administration & dosage ; Cardiomyopathies - prevention & control ; Chronic ; Coxsackievirus ; Coxsackievirus B3 ; Coxsackievirus Infections - prevention & control ; Cysteine Endopeptidases ; Disease Models, Animal ; Enterovirus ; Enterovirus B, Human - drug effects ; Enterovirus B, Human - enzymology ; Heart - virology ; Heart Function Tests ; Inhibitors ; Male ; Mice, Inbred DBA ; Myocarditis ; Protease Inhibitors - administration & dosage ; Survival Analysis ; Treatment Outcome ; Viral Load ; Viral Proteins - antagonists & inhibitors</subject><ispartof>Virus research, 2015-03, Vol.199, p.1-8</ispartof><rights>2014 The Authors</rights><rights>Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c449t-97e03419c88e9ed273fbdb8e53049fd59ec1ccdbe4513d25f71d55debdc4d9f03</citedby><cites>FETCH-LOGICAL-c449t-97e03419c88e9ed273fbdb8e53049fd59ec1ccdbe4513d25f71d55debdc4d9f03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S016817021400505X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25485472$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lim, Byung-Kwan</creatorcontrib><creatorcontrib>Yun, Soo-Hyeon</creatorcontrib><creatorcontrib>Ju, Eun-Seon</creatorcontrib><creatorcontrib>Kim, Bo-Kyoung</creatorcontrib><creatorcontrib>Lee, You-Jung</creatorcontrib><creatorcontrib>Yoo, Dong-Kyeom</creatorcontrib><creatorcontrib>Kim, Young-Chul</creatorcontrib><creatorcontrib>Jeon, Eun-Seok</creatorcontrib><title>Soluble Coxsackievirus B3 3C Protease Inhibitor Prevents Cardiomyopathy in an Experimental Chronic Myocarditis Murine Model</title><title>Virus research</title><addtitle>Virus Res</addtitle><description>•Re-established the chronic CVB3 myocarditis animal model for drug administration.•Produced water-soluble 3CPI by chemically modifying the water-insoluble 3CPI.•3CPI inhibited virus replication in various organs, myocardial damage, and reduced mortality.•Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.
Coxsackievirus B3 (CVB3) is a common cause of myocarditis and dilated cardiomyopathy. CVB3 3C protease (3CP) cleaves the viral polyprotein during replication. We tested whether a water soluble 3CP inhibitor (3CPI) had antiviral effects in a chronic myocarditis model.
Chronic myocarditis was established using DBA/2 strain mice. Starting on post-infection (p.i) day 3, CVB3-infected mice (n=41) were treated with 3CPI by daily intraperitoneal (i.p.) injection at a concentration of 50μM (1.7mg/kg/day) per day for 3 consecutive days. Additional mice (n=49) were injected with PBS as a control.
The 5-week survival rate was significantly higher with 3CPI treatment (82.3% versus 47.9%; P<0.05). Organ virus titers at day 3 and 7 and myocardial damage were significantly lower in 3CPI-treated mice. Echocardiography at day 31 indicated strong protection of heart function by 3CPI (FS, 51.2±1.5 versus 26.1±1.5%; P<0.001). Hemodynamic measurements indicated that 3CPI treatment markedly reduced CVB3-induced LV dysfunction on day 31 (dP/dTmax, 5302±352 versus 4103±408mmHg/s, P<0.05; dP/dTmin, −3798±212 versus −2814±206mmHg/s, P<0.01).
Water soluble 3CPI was delivered through i.p. injection after CVB3 infection. This agent preserved heart function and decreased organ viral titers and myocardial damage. Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.</description><subject>3C Viral Proteases</subject><subject>Animals</subject><subject>Antiviral agent</subject><subject>Antiviral Agents - administration & dosage</subject><subject>Cardiomyopathies - prevention & control</subject><subject>Chronic</subject><subject>Coxsackievirus</subject><subject>Coxsackievirus B3</subject><subject>Coxsackievirus Infections - prevention & control</subject><subject>Cysteine Endopeptidases</subject><subject>Disease Models, Animal</subject><subject>Enterovirus</subject><subject>Enterovirus B, Human - drug effects</subject><subject>Enterovirus B, Human - enzymology</subject><subject>Heart - virology</subject><subject>Heart Function Tests</subject><subject>Inhibitors</subject><subject>Male</subject><subject>Mice, Inbred DBA</subject><subject>Myocarditis</subject><subject>Protease Inhibitors - administration & dosage</subject><subject>Survival Analysis</subject><subject>Treatment Outcome</subject><subject>Viral Load</subject><subject>Viral Proteins - antagonists & inhibitors</subject><issn>0168-1702</issn><issn>1872-7492</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFu1DAQhi0EokvhFSofuSR4bCeOb0DUQqWuQALOVmJPtF6y8WInq654ebzdlmtPI42-f0YzHyFXwEpgUH_YlgcflxQxlZyBLAFKJtgLsoJG8UJJzV-SVQabAhTjF-RNSlvGWC1U_Zpc8Eo2lVR8Rf7-COPSj0jbcJ86-9vjw1z6WVDR0u8xzNglpLfTxvd-DjG38IDTnGjbRefD7hj23bw5Uj_RbqLX93uMfpeBbqTtJobJW7o-BnuCZ5_oeol-QroODse35NXQjQnfPdZL8uvm-mf7tbj79uW2_XRXWCn1XGiFTEjQtmlQo-NKDL3rG6wEk3pwlUYL1roeZQXC8WpQ4KrKYe-sdHpg4pK8P8_dx_BnwTSbnU8Wx7GbMCzJgOKq1g3U6nm0rkEIqR7Q-ozaGFIWMZh9vryLRwPMnByZrXlyZE6ODIDJjnLw6nHH0u_Q_Y89ScnAxzOA-SkHj9Ek63Gy6HxEOxsX_HM7_gF666jl</recordid><startdate>20150302</startdate><enddate>20150302</enddate><creator>Lim, Byung-Kwan</creator><creator>Yun, Soo-Hyeon</creator><creator>Ju, Eun-Seon</creator><creator>Kim, Bo-Kyoung</creator><creator>Lee, You-Jung</creator><creator>Yoo, Dong-Kyeom</creator><creator>Kim, Young-Chul</creator><creator>Jeon, Eun-Seok</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7U7</scope><scope>7U9</scope><scope>C1K</scope><scope>H94</scope></search><sort><creationdate>20150302</creationdate><title>Soluble Coxsackievirus B3 3C Protease Inhibitor Prevents Cardiomyopathy in an Experimental Chronic Myocarditis Murine Model</title><author>Lim, Byung-Kwan ; Yun, Soo-Hyeon ; Ju, Eun-Seon ; Kim, Bo-Kyoung ; Lee, You-Jung ; Yoo, Dong-Kyeom ; Kim, Young-Chul ; Jeon, Eun-Seok</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c449t-97e03419c88e9ed273fbdb8e53049fd59ec1ccdbe4513d25f71d55debdc4d9f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>3C Viral Proteases</topic><topic>Animals</topic><topic>Antiviral agent</topic><topic>Antiviral Agents - administration & dosage</topic><topic>Cardiomyopathies - prevention & control</topic><topic>Chronic</topic><topic>Coxsackievirus</topic><topic>Coxsackievirus B3</topic><topic>Coxsackievirus Infections - prevention & control</topic><topic>Cysteine Endopeptidases</topic><topic>Disease Models, Animal</topic><topic>Enterovirus</topic><topic>Enterovirus B, Human - drug effects</topic><topic>Enterovirus B, Human - enzymology</topic><topic>Heart - virology</topic><topic>Heart Function Tests</topic><topic>Inhibitors</topic><topic>Male</topic><topic>Mice, Inbred DBA</topic><topic>Myocarditis</topic><topic>Protease Inhibitors - administration & dosage</topic><topic>Survival Analysis</topic><topic>Treatment Outcome</topic><topic>Viral Load</topic><topic>Viral Proteins - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lim, Byung-Kwan</creatorcontrib><creatorcontrib>Yun, Soo-Hyeon</creatorcontrib><creatorcontrib>Ju, Eun-Seon</creatorcontrib><creatorcontrib>Kim, Bo-Kyoung</creatorcontrib><creatorcontrib>Lee, You-Jung</creatorcontrib><creatorcontrib>Yoo, Dong-Kyeom</creatorcontrib><creatorcontrib>Kim, Young-Chul</creatorcontrib><creatorcontrib>Jeon, Eun-Seok</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Virus research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lim, Byung-Kwan</au><au>Yun, Soo-Hyeon</au><au>Ju, Eun-Seon</au><au>Kim, Bo-Kyoung</au><au>Lee, You-Jung</au><au>Yoo, Dong-Kyeom</au><au>Kim, Young-Chul</au><au>Jeon, Eun-Seok</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Soluble Coxsackievirus B3 3C Protease Inhibitor Prevents Cardiomyopathy in an Experimental Chronic Myocarditis Murine Model</atitle><jtitle>Virus research</jtitle><addtitle>Virus Res</addtitle><date>2015-03-02</date><risdate>2015</risdate><volume>199</volume><spage>1</spage><epage>8</epage><pages>1-8</pages><issn>0168-1702</issn><eissn>1872-7492</eissn><abstract>•Re-established the chronic CVB3 myocarditis animal model for drug administration.•Produced water-soluble 3CPI by chemically modifying the water-insoluble 3CPI.•3CPI inhibited virus replication in various organs, myocardial damage, and reduced mortality.•Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.
Coxsackievirus B3 (CVB3) is a common cause of myocarditis and dilated cardiomyopathy. CVB3 3C protease (3CP) cleaves the viral polyprotein during replication. We tested whether a water soluble 3CP inhibitor (3CPI) had antiviral effects in a chronic myocarditis model.
Chronic myocarditis was established using DBA/2 strain mice. Starting on post-infection (p.i) day 3, CVB3-infected mice (n=41) were treated with 3CPI by daily intraperitoneal (i.p.) injection at a concentration of 50μM (1.7mg/kg/day) per day for 3 consecutive days. Additional mice (n=49) were injected with PBS as a control.
The 5-week survival rate was significantly higher with 3CPI treatment (82.3% versus 47.9%; P<0.05). Organ virus titers at day 3 and 7 and myocardial damage were significantly lower in 3CPI-treated mice. Echocardiography at day 31 indicated strong protection of heart function by 3CPI (FS, 51.2±1.5 versus 26.1±1.5%; P<0.001). Hemodynamic measurements indicated that 3CPI treatment markedly reduced CVB3-induced LV dysfunction on day 31 (dP/dTmax, 5302±352 versus 4103±408mmHg/s, P<0.05; dP/dTmin, −3798±212 versus −2814±206mmHg/s, P<0.01).
Water soluble 3CPI was delivered through i.p. injection after CVB3 infection. This agent preserved heart function and decreased organ viral titers and myocardial damage. Soluble 3CPI may be beneficial in the treatment of cardiomyopathy associated with enterovirus infection.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>25485472</pmid><doi>10.1016/j.virusres.2014.11.030</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3C Viral Proteases Animals Antiviral agent Antiviral Agents - administration & dosage Cardiomyopathies - prevention & control Chronic Coxsackievirus Coxsackievirus B3 Coxsackievirus Infections - prevention & control Cysteine Endopeptidases Disease Models, Animal Enterovirus Enterovirus B, Human - drug effects Enterovirus B, Human - enzymology Heart - virology Heart Function Tests Inhibitors Male Mice, Inbred DBA Myocarditis Protease Inhibitors - administration & dosage Survival Analysis Treatment Outcome Viral Load Viral Proteins - antagonists & inhibitors |
| title | Soluble Coxsackievirus B3 3C Protease Inhibitor Prevents Cardiomyopathy in an Experimental Chronic Myocarditis Murine Model |
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