Tweet
J Virol. 2013 Jan 2. [Epub ahead of print]
5-(Perylen-3-yl)ethynyl-arabino-uridine (aUY11), an arabino-based rigid amphipathic fusion inhibitor, targets virion envelope lipids to inhibit fusion of influenza, hepatitis C and other enveloped viruses.
Colpitts CC, Ustinov AV, Epand RF, Epand RM, Korshun VA, Schang LM.
Source
Department of Medical Microbiology and Immunology.
Abstract
Entry of enveloped viruses requires fusion of viral and cellular membranes. Fusion requires the formation of an intermediate stalk structure, in which only the outer leaflets are fused. The stalk structure in turn requires the lipid bilayer of the envelope to bend into negative curvature. This process is inhibited by enrichment in the outer leaflet of lipids with larger polar headgroups, which favour positive curvature. Accordingly, phospholipids with such shape inhibit viral fusion. We previously identified a compound, 5-(perylen-3-yl)ethynyl-2' -deoxy-uridine (dUY11), with overall similar shape and amphipathicity to these phospholipids. dUY11 inhibited the formation of the negative curvature necessary for stalk formation and the fusion of a model enveloped virus, VSV. We proposed that dUY11 acted by biophysical mechanisms as a result of its shape and amphipathicity. To test this model, we now characterized the mechanisms against influenza and HCV of 5-(perylen-3-yl)ethynyl-arabino-uridine (aUY11), which has similar shape and amphipathicity to dUY11 but contains an arabino-nucleoside. aUY11 interacted with envelope lipids to inhibit the infectivity of influenza, HCV, HSV-1/-2 and other enveloped viruses. It specifically inhibited the fusion of influenza, HCV, VSV, and even protein-free liposomes, to cells. Furthermore, aUY11 inhibited the formation of negative curvature in model lipid bilayers. In summary, the arabino-derived aUY11 and the deoxy-derived dUY11 act by the same antiviral mechanisms against several enveloped but otherwise unrelated viruses. Therefore, chemically unrelated compounds of appropriate shape and amphipathicity target virion envelope lipids to inhibit formation of the negative curvature required for fusion, inhibiting infectivity by biophysical, not biochemical, mechanisms.
PMID:
23283943
[PubMed - as supplied by publisher]
5-(Perylen-3-yl)ethynyl-arabino-uridine (aUY11), an arabino-based rigid amphipathic fusion inhibitor, targets virion envelope lipids to inhibit fusion of influenza, hepatitis C and other enveloped viruses.
Colpitts CC, Ustinov AV, Epand RF, Epand RM, Korshun VA, Schang LM.
Source
Department of Medical Microbiology and Immunology.
Abstract
Entry of enveloped viruses requires fusion of viral and cellular membranes. Fusion requires the formation of an intermediate stalk structure, in which only the outer leaflets are fused. The stalk structure in turn requires the lipid bilayer of the envelope to bend into negative curvature. This process is inhibited by enrichment in the outer leaflet of lipids with larger polar headgroups, which favour positive curvature. Accordingly, phospholipids with such shape inhibit viral fusion. We previously identified a compound, 5-(perylen-3-yl)ethynyl-2' -deoxy-uridine (dUY11), with overall similar shape and amphipathicity to these phospholipids. dUY11 inhibited the formation of the negative curvature necessary for stalk formation and the fusion of a model enveloped virus, VSV. We proposed that dUY11 acted by biophysical mechanisms as a result of its shape and amphipathicity. To test this model, we now characterized the mechanisms against influenza and HCV of 5-(perylen-3-yl)ethynyl-arabino-uridine (aUY11), which has similar shape and amphipathicity to dUY11 but contains an arabino-nucleoside. aUY11 interacted with envelope lipids to inhibit the infectivity of influenza, HCV, HSV-1/-2 and other enveloped viruses. It specifically inhibited the fusion of influenza, HCV, VSV, and even protein-free liposomes, to cells. Furthermore, aUY11 inhibited the formation of negative curvature in model lipid bilayers. In summary, the arabino-derived aUY11 and the deoxy-derived dUY11 act by the same antiviral mechanisms against several enveloped but otherwise unrelated viruses. Therefore, chemically unrelated compounds of appropriate shape and amphipathicity target virion envelope lipids to inhibit formation of the negative curvature required for fusion, inhibiting infectivity by biophysical, not biochemical, mechanisms.
PMID:
23283943
[PubMed - as supplied by publisher]
