Inhibition of cellular entry of lymphocytic choriomeningitis virus by amphipathic DNA polymers

Abstract

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.

Targeting the Proteolytic Processing of the Viral Glycoprotein Precursor Is a Promising Novel Antiviral Strategy against Arenaviruses

“…Recently, we and others have identified novel classes of arenavirus entry inhibitors, including DNA aptamers (19) and several potent small-molecule inhibitors (3,20). While such entry inhibitors are likely efficacious early in infection, they are rather ineffective once the host cell has become infected.…”

Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

“…The presence of sequence-independent antiviral activity with PS-ONs in HSV has been previously described (10,12,13). Recently, this sequenceindependent antiviral activity of PS-ONs was more clearly elucidated in HSV and other viruses (17,22,27) and was shown to be derived from the chemical nature of PS-ONs amphipathic polymers, independent of the stability that phosphorothioation provides to oligonucleotides. Furthermore, the antiherpetic activity of amphipathic polymers (APs) in herpes simplex virus (HSV) and HIV was due not only to blocking virus binding but also to virus entry (17,27).…”

Nucleic Acid Polymers Prevent the Establishment of Duck Hepatitis B Virus Infection In Vivo

“…For example, NAPs have been shown to interact with prion proteins (12) and type 1 viral fusion glycoproteins in both human immunodeficiency virus type 1 (HIV-1) and lymphocytic choriomeningitis virus (LCMV) (13,14). In the case of viral entry, NAP-protein interactions destroy the ability of amphipathic protein domains present in viral fusion glycoproteins to interact with each other, a process known to be important in catalyzing the entry of many enveloped viruses into their host cells (15).…”

“…In the case of viral entry, NAP-protein interactions destroy the ability of amphipathic protein domains present in viral fusion glycoproteins to interact with each other, a process known to be important in catalyzing the entry of many enveloped viruses into their host cells (15). In HIV-1 and LCMV, the interaction of NAPs with viral fusion proteins is consistent with their ability to block viral entry, and they have little or no postentry antiviral activity (13,14).…”