title: Investigating the efficacy of pamidronate, a chemical inhibitor of farnesyl pyrophosphate synthase, in the inhibition of influenza virus infection in vitro and in vivo.
abstract: Influenza A virus has caused significant pandemics in the past decades, including the H1N1‑2009 pandemic. Viperin is an interferon‑inducible protein that acts as a broad‑spectrum antiviral protein via the inhibition of farnesyl pyrophosphate synthase (FPPS). To mimic this activity of viperin, the present study investigated the effectiveness of a commercially available FPPS inhibitor (pamidronate) as an inhibitor of influenza virus infection in vitro and in vivo. HeLaM cells were treated with pamidronate to determine its effect on the replication of influenza virus A/H1N1/WSN/1933. C57BL/6 mice were also subjected to intratracheal pamidronate treatment regimes prior to and following lethal influenza challenge. Treatment with the FPPS inhibitor in vitro resulted in a considerable reduction in the viral titer of ~1 log and diminished lipid raft formation without cellular toxicity, thus mimicking the antiviral effect of viperin. However, pamidronate lacked efficacy in vivo and was associated with increased pulmonary damage, most likely due to the complexity of drug‑host interactions in the infected mice. Further studies are warranted on pamidronate treatment in other infectious diseases that are more susceptible to FPPS inhibition.
authors.affiliation: Host And Pathogen Interactivity Laboratory, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore.
authors.forename: Kai Sen
authors.initials: KS
authors.lastname: Tan
authors.forename: Wai Chii
authors.initials: WC
authors.lastname: Ng
authors.forename: Ju Ee
authors.initials: JE
authors.lastname: Seet
authors.forename: Farzad
authors.initials: F
authors.lastname: Olfat
authors.forename: Bevin P
authors.initials: BP
authors.lastname: Engelward
authors.forename: Vincent T K
authors.initials: VT
authors.lastname: Chow
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000201:enzymology; D021962:Membrane Microdomains / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000401:mortality; D000077268:Pamidronate; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004164:Diphosphonates; D053594:Myeloid Differentiation Factor 88; D014764:Viral Proteins; D051228:Geranyltranstransferase; D000077268:Pamidronate