Antiviral effects of apolipoprotein A-I and its synthetic amphipathic peptide analogs.
Apolipoprotein A-I (apo A-I), the major protein component of serum high density lipoproteins, was found to inhibit herpes simplex virus (HSV)-induced cell fusion at physiological (approximately 1 microM) concentrations. An 18 amino acid-long synthetic amphipathic alpha-helical peptide analog of apo A-I (18A) was also found to inhibit HSV-induced cell fusion at similar concentration (approximately 2 microM). Dimers of 18A connected via a proline (37pA) or an alanine (37aA) residue also inhibited virus-induced cell fusion at similar concentration, suggesting that the presence of a proline turn does not influence the antiviral activity of the amphipathic peptides. However, a peptide analog 18R, in which the distribution of charged residues was reversed, inhibited virus-induced cell fusion only at a higher (approximately 125 microM) concentration, suggesting that the anti-viral activity of the amphipathic peptide is strongly influenced by the nature of the charge distribution at the polar-nonpolar interface. Consistent with their ability to inhibit virus-induced cell fusion, the peptides inhibited the spread of HSV infection as demonstrated by a 10-fold reduction in the virus yield, when virus-infected cells were maintained in the presence of amphipathic peptides. The amphipathic peptides also inhibited penetration of virus into cells, but did not exert any effect on virus adsorption. A nearly complete inhibition of virus penetration was observed when the virus, or both virus and cells, was pretreated with the peptide, suggesting that the peptides may have a direct effect on the virus. The results indicate that amphipathic helices may be useful in designing novel antiviral agents that inhibit penetration and spread of enveloped viruses.
Srinivas
R V
RV
Department of Microbiology, University of Alabama, Birmingham 35294.
Birkedal
B
B
Owens
R J
RJ
Anantharamaiah
G M
GM
Segrest
J P
JP
Compans
R W
RW
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents; D016632:Apolipoprotein A-I; D001054:Apolipoproteins A / Q000494:pharmacology*; D006561:Herpes Simplex / Q000188:drug therapy; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology; D011487:Protein Conformation; D018139:Simplexvirus / Q000187:drug effects* / Q000648:ultrastructure; D014709:Vero Cells
D000998:Antiviral Agents; D016632:Apolipoprotein A-I; D001054:Apolipoproteins A; D010455:Peptides