Potent inhibition of viral fusion by the lipophosphoglycan of Leishmania donovani.
Lipophosphoglycan (LPG) is an amphiphile produced by Leishmania. Its chemical structure consists of a hydrophilic flexible polymer of repeating PO4-6Gal beta 1-4Man alpha 1 units (on average 16 units) linked via a hexasaccharide core to a lyso-1-O-alkyl-P1 membrane anchor. In the study of viral fusion we report in this paper, we have introduced LPG into human erythrocyte ghost (HEG) membranes, with the purpose of understanding how the LPG-induced surface-structural changes may modulate the interactions between a viral envelope and the HEG membranes. We have found that LPG, when incorporated at very low concentrations into intact human erythrocyte membranes, strongly inhibits Sendai virus-induced hemolysis. When incorporated into HEGs, it reduces the binding of both Sendai and influenza viruses to HEGs; furthermore, it strongly inhibits the overall viral fusion to HEGs, being among the most potent known inhibitors. We have also shown that LPG stabilizes the bilayer structure of phosphatidylethanolamine against the formation of an inverted-hexagonal structure. We suggest that LPG may give rise to an effective "steric repulsion" between the viral and HEG membranes, thereby modulating some specific modes of interaction between viral-target membranes in the overall fusion process; LPG may also modulate the bending rigidity and the spontaneous curvature of the HEG membrane in the direction of making the destabilization and rearrangement of the underlying lipid bilayer more difficult.
Miao
L
L
Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
Stafford
A
A
Nir
S
S
Turco
S J
SJ
Flanagan
T D
TD
Epand
R M
RM
D000818:Animals; D002240:Carbohydrate Sequence; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000821:virology; D006028:Glycosphingolipids / Q000494:pharmacology*; D006461:Hemolysis; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D007700:Kinetics; D007893:Leishmania donovani / Q000737:chemistry*; D008081:Liposomes; D008561:Membrane Fusion / Q000187:drug effects*; D008969:Molecular Sequence Data; D010222:Parainfluenza Virus 1, Human / Q000502:physiology*; D011991:Receptors, Virus / Q000187:drug effects; D013696:Temperature
D006028:Glycosphingolipids; D008081:Liposomes; D011991:Receptors, Virus; C008290:lipophosphonoglycan