Inhibitory Activity of Synthetic Peptide Antibiotics on Feline Immunodeficiency Virus Infectivity In Vitro

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Published in:	Journal of Virology Vol. 76; no. 19; pp. 9952 - 9961
Main Authors:	Ma, Jia, Kennedy-Stoskopf, Suzanne, Jaynes, Jesse M, Thurmond, Linda M, Tompkins, Wayne A
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 01-10-2002
Subjects:	Amino Acid Sequence Animals Antiviral Agents - pharmacology Cats gag Gene Products, Human Immunodeficiency Virus Gene Products, gag - analysis HIV Antigens - analysis Immunodeficiency Virus, Feline - drug effects Molecular Sequence Data Peptides - pharmacology Protein Structure, Secondary Reverse Transcriptase Inhibitors - pharmacology RNA, Messenger - analysis Vaccines and Antiviral Agents Virus Assembly - drug effects Virus Replication - drug effects
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Abstract	Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue JVI About JVI Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy JVI RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0022-538X Online ISSN: 1098-5514 Copyright © 2014 by the American Society for Microbiology. For an alternate route to JVI .asm.org, visit: JVI
AbstractList	Natural peptide antibiotics are part of host innate immunity against a wide range of microbes, including some viruses. Synthetic peptides modeled after natural peptide antibiotics interfere with microbial membranes and are termed peptidyl membrane-interactive molecules (peptidyl-MIM (Demegen Inc, Pittsburgh, Pa.)). Sixteen peptidyl-MIM candidates were tested for activity against feline immunodeficiency virus (FIV) on infected CrFK cells. Three of them (D4E1, DC1, and D1D6) showed potent anti-FIV activity in chronically infected CrFK cells as measured by decreased reverse transcriptase (RT) activity, having 50% inhibitory concentrations of 0.46, 0.75, and 0.94 mu M, respectively, which were approximately 10 times lower than their direct cytotoxic concentrations. Treatment of chronically infected CrFK cells with 2 mu M D4E1 for 3 days completely reversed virus-induced cytopathic effect. Immunofluorescence revealed reduced p26 staining in these cells. Treatment of chronically infected CrFK cells with 2 mu M D4E1 suppressed virus production ([~]50%) for up to 7 days, The virions from the D4E1-treated culture had impaired infectivity, as measured by the 50% tissue culture infectious dose and nested PCR analysis of proviral DNA. However, these noninfectious virions were able to bind and internalize, suggesting a defect at some postentry step. After chronically infected CrFK cells were treated with D4E1 for 24 h, increased cell-associated mature p26 Gag and decreased extracellular virus-associated p26 Gag were observed by Western blot analysis, suggesting that virus assembly and/or release may be blocked by D4E1 treatment, whereas virus binding, penetration, RNA synthesis, and protein synthesis appear to be unaffected. Synthetic peptide antibiotics may be useful tools in the search for antiviral drugs having a wide therapeutic window for host cells. Natural peptide antibiotics are part of host innate immunity against a wide range of microbes, including some viruses. Synthetic peptides modeled after natural peptide antibiotics interfere with microbial membranes and are termed peptidyl membrane-interactive molecules (peptidyl-MIM [Demegen Inc, Pittsburgh, Pa.]). Sixteen peptidyl-MIM candidates were tested for activity against feline immunodeficiency virus (FIV) on infected CrFK cells. Three of them (D4E1, DC1, and D1D6) showed potent anti-FIV activity in chronically infected CrFK cells as measured by decreased reverse transcriptase (RT) activity, having 50% inhibitory concentrations of 0.46, 0.75, and 0.94 micro M, respectively, which were approximately 10 times lower than their direct cytotoxic concentrations. Treatment of chronically infected CrFK cells with 2 micro M D4E1 for 3 days completely reversed virus-induced cytopathic effect. Immunofluorescence revealed reduced p26 staining in these cells. Treatment of chronically infected CrFK cells with 2 micro M D4E1 suppressed virus production ( approximately 50%) for up to 7 days, The virions from the D4E1-treated culture had impaired infectivity, as measured by the 50% tissue culture infectious dose and nested PCR analysis of proviral DNA. However, these noninfectious virions were able to bind and internalize, suggesting a defect at some postentry step. After chronically infected CrFK cells were treated with D4E1 for 24 h, increased cell-associated mature p26 Gag and decreased extracellular virus-associated p26 Gag were observed by Western blot analysis, suggesting that virus assembly and/or release may be blocked by D4E1 treatment, whereas virus binding, penetration, RNA synthesis, and protein synthesis appear to be unaffected. Synthetic peptide antibiotics may be useful tools in the search for antiviral drugs having a wide therapeutic window for host cells. Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue JVI About JVI Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy JVI RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0022-538X Online ISSN: 1098-5514 Copyright © 2014 by the American Society for Microbiology. For an alternate route to JVI .asm.org, visit: JVI ABSTRACT Natural peptide antibiotics are part of host innate immunity against a wide range of microbes, including some viruses. Synthetic peptides modeled after natural peptide antibiotics interfere with microbial membranes and are termed peptidyl membrane-interactive molecules (peptidyl-MIM [Demegen Inc, Pittsburgh, Pa.]). Sixteen peptidyl-MIM candidates were tested for activity against feline immunodeficiency virus (FIV) on infected CrFK cells. Three of them (D4E1, DC1, and D1D6) showed potent anti-FIV activity in chronically infected CrFK cells as measured by decreased reverse transcriptase (RT) activity, having 50% inhibitory concentrations of 0.46, 0.75, and 0.94 μM, respectively, which were approximately 10 times lower than their direct cytotoxic concentrations. Treatment of chronically infected CrFK cells with 2 μM D4E1 for 3 days completely reversed virus-induced cytopathic effect. Immunofluorescence revealed reduced p26 staining in these cells. Treatment of chronically infected CrFK cells with 2 μM D4E1 suppressed virus production (∼50%) for up to 7 days, The virions from the D4E1-treated culture had impaired infectivity, as measured by the 50% tissue culture infectious dose and nested PCR analysis of proviral DNA. However, these noninfectious virions were able to bind and internalize, suggesting a defect at some postentry step. After chronically infected CrFK cells were treated with D4E1 for 24 h, increased cell-associated mature p26 Gag and decreased extracellular virus-associated p26 Gag were observed by Western blot analysis, suggesting that virus assembly and/or release may be blocked by D4E1 treatment, whereas virus binding, penetration, RNA synthesis, and protein synthesis appear to be unaffected. Synthetic peptide antibiotics may be useful tools in the search for antiviral drugs having a wide therapeutic window for host cells. Natural peptide antibiotics are part of host innate immunity against a wide range of microbes, including some viruses. Synthetic peptides modeled after natural peptide antibiotics interfere with microbial membranes and are termed peptidyl membrane-interactive molecules (peptidyl-MIM [Demegen Inc, Pittsburgh, Pa.]). Sixteen peptidyl-MIM candidates were tested for activity against feline immunodeficiency virus (FIV) on infected CrFK cells. Three of them (D4E1, DC1, and D1D6) showed potent anti-FIV activity in chronically infected CrFK cells as measured by decreased reverse transcriptase (RT) activity, having 50% inhibitory concentrations of 0.46, 0.75, and 0.94 μM, respectively, which were approximately 10 times lower than their direct cytotoxic concentrations. Treatment of chronically infected CrFK cells with 2 μM D4E1 for 3 days completely reversed virus-induced cytopathic effect. Immunofluorescence revealed reduced p26 staining in these cells. Treatment of chronically infected CrFK cells with 2 μM D4E1 suppressed virus production (∼50%) for up to 7 days, The virions from the D4E1-treated culture had impaired infectivity, as measured by the 50% tissue culture infectious dose and nested PCR analysis of proviral DNA. However, these noninfectious virions were able to bind and internalize, suggesting a defect at some postentry step. After chronically infected CrFK cells were treated with D4E1 for 24 h, increased cell-associated mature p26 Gag and decreased extracellular virus-associated p26 Gag were observed by Western blot analysis, suggesting that virus assembly and/or release may be blocked by D4E1 treatment, whereas virus binding, penetration, RNA synthesis, and protein synthesis appear to be unaffected. Synthetic peptide antibiotics may be useful tools in the search for antiviral drugs having a wide therapeutic window for host cells.
Author	Jia Ma Jesse M. Jaynes Suzanne Kennedy-Stoskopf Linda M. Thurmond Wayne A. Tompkins
AuthorAffiliation	Department of Microbiology, Pathology and Parasitology, North Carolina State University, Raleigh, North Carolina, 1 Demegen, Inc., Pittsburgh, Pennsylvania, 2 Glaxo SmithKline Inc., Research Triangle Park, North Carolina 3
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Notes	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Corresponding author. Present address: Glaxo SmithKline, EH.A2217C.2G, 5 Moore Dr., Research Triangle Park, NC 27709. Phone: (919) 483-8440. Fax: (919) 315-6003. E-mail: jzm83081@gsk.com.
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Snippet	Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley... Natural peptide antibiotics are part of host innate immunity against a wide range of microbes, including some viruses. Synthetic peptides modeled after natural... ABSTRACT Natural peptide antibiotics are part of host innate immunity against a wide range of microbes, including some viruses. Synthetic peptides modeled...
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SubjectTerms	Amino Acid Sequence Animals Antiviral Agents - pharmacology Cats gag Gene Products, Human Immunodeficiency Virus Gene Products, gag - analysis HIV Antigens - analysis Immunodeficiency Virus, Feline - drug effects Molecular Sequence Data Peptides - pharmacology Protein Structure, Secondary Reverse Transcriptase Inhibitors - pharmacology RNA, Messenger - analysis Vaccines and Antiviral Agents Virus Assembly - drug effects Virus Replication - drug effects
Title	Inhibitory Activity of Synthetic Peptide Antibiotics on Feline Immunodeficiency Virus Infectivity In Vitro
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