Synthesis of 1-β-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole and its in vitro and in vivo efficacy against Hantavirus

Dong Hoon Chung, Sidath C. Kumarapperuma, Yanjie Sun, Qianjun Li, Yong Kyu Chu, Jeffrey B. Arterburn, William B. Parker, Jeffrey Smith, Kristin Spik, Harish N. Ramanathan, Connie S. Schmaljohn, Colleen B. Jonsson

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38 Scopus citations

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-β-ribosides and identified one with antiviral activity, 1-β-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole (ETAR). ETAR showed an EC50 value of 10 and 4.4 μM 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 ∼25% survival at 12.5 and 25 mg/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.

Original languageEnglish (US)
Pages (from-to)19-27
Number of pages9
JournalAntiviral Research
Volume79
Issue number1
DOIs
StatePublished - Jul 2008

Bibliographical note

Funding Information:
This work was supported in part by NIH grant R21 AI064499-01 and a contract from the Department of Defense USAMRC W81XWH-04-C-0055 (PI Jonsson). We thank Ms. Feng Shuang at Southern Research Institute for statistical analyses. We thank Meredith James, Dana Skillman, Candi Looney, Donna Bowen, Robert Wood and Rodney Donaldson for technical support in the BSL3 animal studies.

Keywords

  • Andes virus
  • Crimean Congo hemorrhagic fever virus
  • HFRS
  • Hantaan virus HTNV
  • Hemorrhagic fever with renal syndrome
  • Ribavirin
  • Rift Valley fever virus

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