Inhibitory activity of synthetic peptide antibiotics on feline immunodeficiency virus infectivity in vitro.
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.
Department of Microbiology, Pathology and Parasitology, North Carolina State University, Raleigh, North Carolina, USA. jzm83081@gsk.com
Jia
J
Ma
Suzanne
S
Kennedy-Stoskopf
Jesse M
JM
Jaynes
Linda M
LM
Thurmond
Wayne A
WA
Tompkins
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002415:Cats; D015683:Gene Products, gag / Q000032:analysis; D015488:HIV Antigens / Q000032:analysis; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects*; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000032:analysis; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D019065:Virus Assembly / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D015683:Gene Products, gag; D015488:HIV Antigens; D010455:Peptides; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; C065558:gag protein p26, Human immunodeficiency virus