title: Antiviral effect of ranpirnase against Ebola virus.
abstract: The recent epidemic of Ebola has intensified the need for the development of novel antiviral therapeutics that prolong and improve survival against deadly viral diseases. We sought to determine whether ranpirnase, an endoribonuclease from Rana pipiens with a demonstrated human safety profile in phase III oncology trials, can reduce titers of Ebola virus (EBOV) in infected cells, protect mice against mouse-adapted EBOV challenge, and reduce virus levels in infected mice. Our results demonstrate that 0.50 μg/ml ranpirnase is potently effective at reducing EBOV Zaire Kikwit infection in cultured Vero E6 cells (Selectivity Index 47.8-70.2). In a prophylactic study, a single intravenous dose of 0.1 mg/kg ranpirnase protected 70% of mice from progressive infection. Additionally, in a post-exposure prophylactic study, 100% of female mice survived infection after intraperitoneal administration of 0.1 mg/kg ranpirnase for ten days beginning 1 h post challenge. Most of the male counterparts were sacrificed due to weight loss by Study Day 8 or 9; however, the Clinical Activity/Behavior scores of these mice remained low and no significant microscopic pathologies could be detected in the kidneys, livers or spleens. Furthermore, live virus could not be detected in the sera of ranpirnase-treated mice by Study Day 8 or in the kidneys, livers or spleens by Study Day 12, and viral RNA levels declined exponentially by Study Day 12. Because ranpirnase is exceptionally stable and has a long track record of safe intravenous administration to humans, this drug provides a promising new candidate for clinical consideration in the treatment of Ebola virus disease alone or in combination with other therapeutics.
authors.affiliation: Tamir Biotechnology, 12625 High Bluff Dr, Suite 113, San Diego, CA 92130, USA. Electronic address: thodge@tamirbio.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hodge
authors.affiliation: Tamir Biotechnology, 12625 High Bluff Dr, Suite 113, San Diego, CA 92130, USA. Electronic address: kgdrap@netscape.net.
authors.forename: Ken
authors.initials: K
authors.lastname: Draper
authors.affiliation: University of Texas Medical Branch (UTMB), 301University Blvd, Galveston, TX 77555, USA. Electronic address: trbrasel@utmb.edu.
authors.forename: Trevor
authors.initials: T
authors.lastname: Brasel
authors.affiliation: University of Texas Medical Branch (UTMB), 301University Blvd, Galveston, TX 77555, USA. Electronic address: anfreibe@utmb.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Freiberg
authors.affiliation: Tamir Biotechnology, 12625 High Bluff Dr, Suite 113, San Diego, CA 92130, USA. Electronic address: lsquiquera@tamirbio.com.
authors.forename: Luis
authors.initials: L
authors.lastname: Squiquera
authors.affiliation: Tamir Biotechnology, 12625 High Bluff Dr, Suite 113, San Diego, CA 92130, USA. Electronic address: dsidrans@jhmi.edu.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: Tamir Biotechnology, 12625 High Bluff Dr, Suite 113, San Diego, CA 92130, USA. Electronic address: jsulley@tamirbio.com.
authors.forename: Jamie
authors.initials: J
authors.lastname: Sulley
authors.affiliation: Tamir Biotechnology, 12625 High Bluff Dr, Suite 113, San Diego, CA 92130, USA. Electronic address: debra.taxman@gmail.com.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Taxman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D029043:Ebolavirus / Q000187:drug effects* / Q000502:physiology; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000401:mortality / Q000821:virology*; D006801:Humans; D051379:Mice; D012367:RNA, Viral; D012260:Ribonucleases / Q000494:pharmacology*; D014709:Vero Cells; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D012260:Ribonucleases; C058703:ranpirnase
keywords: Antiviral; Ebola (EBOV); Ranpirnase