title: Development and evaluation of a host-targeted antiviral that abrogates herpes simplex virus replication through modulation of arginine-associated metabolic pathways.
abstract: Since their inception five decades ago, most antivirals have been engineered to disrupt a single viral protein or process that is essential for viral replication. This approach has limited the overall therapeutic effectiveness and applicability of current antivirals due to restricted viral specificity, a propensity for development of drug resistance, and an inability to control deleterious host-mediated inflammation. As obligate intracellular parasites, viruses are reliant on host metabolism and macromolecular synthesis pathways. Of these biosynthetic processes, many viruses, including Herpes simplex viruses (HSV), are absolutely dependent on the bioavailability of arginine, a non-essential amino acid that is critical for many physiological and pathophysiological processes associated with either facilitating viral replication or progression of disease. To assess if targeting host arginine-associated metabolic pathways would inhibit HSV replication, a pegylated recombinant human Arginase I (peg-ArgI) was generated and its in vitro anti-herpetic activity was evaluated. Cells continuously treated with peg-ArgI for over 48 h exhibited no signs of cytotoxicity or loss of cell viability. The antiviral activity of peg-ArgI displayed a classical dose-response curve with IC50's in the sub-nanomolar range. peg-ArgI potently inhibited HSV-1 and HSV-2 viral replication, infectious virus production, cell-to-cell spread/transmission and virus-mediated cytopathic effects. Not unexpectedly given its host-targeted mechanism of action, peg-ArgI showed similar effectiveness at controlling replication of single and multidrug resistant HSV-1 mutants. These findings illustrate that targeting host arginine-associated metabolic pathways is an effective means of controlling viral replicative processes. Further exploration into the breadth of viruses inhibited by peg-ArgI, as well as the ability of peg-ArgI to suppress arginine-associated virus-mediated pathophysiological disease processes is warranted.
authors.affiliation: Department of Microbiology, Immunology, and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, USA; Department of Pediatrics, School of Medicine, Louisiana State University Health Sciences Center, USA; The Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, USA.
authors.forename: Maria Dulfary
authors.initials: MD
authors.lastname: Sanchez
authors.affiliation: Department of Pediatrics, School of Medicine, Louisiana State University Health Sciences Center, USA; The Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, USA; The Louisiana Vaccine Center, New Orleans, LA, 70112, USA.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Ochoa
authors.affiliation: Department of Microbiology, Immunology, and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, USA; Department of Ophthalmology, School of Medicine, Louisiana State University Health Sciences Center, USA; The Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, USA; The Louisiana Vaccine Center, New Orleans, LA, 70112, USA. Electronic address: tfoste@lsuhsc.edu.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Foster
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001119:Arginase / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D006561:Herpes Simplex / Q000378:metabolism / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects* / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D011994:Recombinant Proteins; D001120:Arginine; C574619:ARG1 protein, human; D001119:Arginase
keywords: Antiviral; Arginase; Arginine; Drug-resistance; HSV-1; HSV-2; Herpes simplex virus; Metabolism