Inhibition of cellular entry of lymphocytic choriomeningitis virus by amphipathic DNA polymers.
The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) represents a powerful experimental model for the study of the basic virology and pathogenesis of arenaviruses. In the present study, we used the LCMV model to evaluate the anti-viral potential of phosphorothioate oligonucleotides against arenaviruses. Our findings indicate that amphipathic DNA polymers (APs) are potent inhibitors of infection with a series of LCMV isolates with IC(50) in the low nanomolar range. APs target the surface glycoprotein (GP) of LCMV and block viral entry and cell-cell propagation of the virus, without affecting later steps in replication or release of progeny virus from infected cells. The anti-viral action of APs is sequence-independent but is critically dependent on their size and hydrophobicity. Mechanistically, we provide evidence that APs disrupt the interaction between LCMVGP and its cellular receptor, alpha-dystroglycan. Exposure of LCMV to APs does not affect the stability of the GP virion spike and has no effect on the conformation of a neutralizing antibody epitope, suggesting rather subtle changes in the conformation and/or conformational dynamics of the viral GP.
Lee
Andrew M
AM
Molecular and Integrative Neurosciences Department (MIND), The Scripps Research Institute, IMM-6, La Jolla, CA 92037, USA.
Rojek
Jillian M
JM
Gundersen
Anette
A
Ströher
Ute
U
Juteau
Jean-Marc
JM
Vaillant
Andrew
A
Kunz
Stefan
S
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D049030:Dystroglycans / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects* / Q000472:pathogenicity; D008562:Membrane Glycoproteins / Q000378:metabolism; D054735:Phosphorothioate Oligonucleotides / Q000494:pharmacology*; D014709:Vero Cells; D053586:Virus Internalization / Q000187:drug effects*
D000998:Antiviral Agents; D008562:Membrane Glycoproteins; D054735:Phosphorothioate Oligonucleotides; D049030:Dystroglycans