title: Synthesis of 1-beta-D-ribofuranosyl-3-ethynyl-[1,2,4]triazole and its in vitro and in vivo efficacy against Hantavirus.
abstract: There are no FDA approved drugs for the treatment of hemorrhagic fever with renal syndrome (HFRS), a serious human illnesses caused by hantaviruses. Clinical studies using ribavirin (RBV) to treat HFRS patients suggest that it provides an improved prognosis when given early in the course of disease. Given the unique antiviral activity of RBV and the lack of other lead scaffolds, we prepared a diverse series of 3-substituted 1,2,4-triazole-beta-ribosides and identified one with antiviral activity, 1-beta-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole (ETAR). ETAR showed an EC(50) value of 10 and 4.4 microM for Hantaan virus (HTNV) and Andes virus, respectively. ETAR had weak activity against Crimean Congo hemorrhagic fever virus, but had no activity against Rift Valley fever virus. Intraperitoneally delivered ETAR offered protection to suckling mice challenged with HTNV with a approximately 25% survival at 12.5 and 25mg/kg ETAR, and a MTD of 17.1+/-0.7 days. ETAR was phosphorylated in Vero E6 cells to its 5'-triphosphate and reduced cellular GTP levels. In contrast to RBV, ETAR did not increase mutation frequency of the HTNV genome, which suggests it has a different mechanism of action than RBV. ETAR is an exciting and promising lead compound that will be elaborated in further synthetic investigations as a framework for the rational design of new antivirals for treatment of HFRS.
authors.affiliation: Department of Biochemistry and Molecular Biology, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Chung
authors.forename: Sidath C
authors.initials: SC
authors.lastname: Kumarapperuma
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Sun
authors.forename: Qianjun
authors.initials: Q
authors.lastname: Li
authors.forename: Yong-Kyu
authors.initials: YK
authors.lastname: Chu
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Arterburn
authors.forename: William B
authors.initials: WB
authors.lastname: Parker
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Smith
authors.forename: Kristin
authors.initials: K
authors.lastname: Spik
authors.forename: Harish N
authors.initials: HN
authors.lastname: Ramanathan
authors.forename: Connie S
authors.initials: CS
authors.lastname: Schmaljohn
authors.forename: Colleen B
authors.initials: CB
authors.lastname: Jonsson
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D005260:Female; D016679:Genome, Viral / Q000187:drug effects; D006151:Guanosine / Q000037:antagonists & inhibitors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D006476:Orthohantavirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006480:Hemorrhagic Fever with Renal Syndrome / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation / Q000187:drug effects; D009705:Nucleosides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D012254:Ribavirin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: C530251:1-ribofuranosyl-3-ethynyl-(1,2,4)triazole; D000998:Antiviral Agents; D009705:Nucleosides; D014230:Triazoles; D006151:Guanosine; D012254:Ribavirin; D006160:Guanosine Triphosphate