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

• Published in: Antiviral research Vol. 79; no. 1; pp. 19 - 27
• Main Authors: Chung, Dong-Hoon, Kumarapperuma, Sidath C., Sun, Yanjie, Li, Qianjun, Chu, Yong-Kyu, Arterburn, Jeffrey B., Parker, William B., Smith, Jeffrey, Spik, Kristin, Ramanathan, Harish N., Schmaljohn, Connie S., Jonsson, Colleen B.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.07.2008; Elsevier
• Subjects: Andes virus; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Biological and medical sciences; Cercopithecus aethiops; Crimean Congo hemorrhagic fever virus; Female; Genome, Viral - drug effects; Guanosine - antagonists & inhibitors; Guanosine - metabolism; Guanosine Triphosphate - antagonists & inhibitors; Guanosine Triphosphate - metabolism; Hantaan virus; Hantaan virus HTNV; Hantavirus; Hantavirus - drug effects; Hantavirus - genetics; Hantavirus - metabolism; Hemorrhagic fever with renal syndrome; Hemorrhagic Fever with Renal Syndrome - drug therapy; Hemorrhagic Fever with Renal Syndrome - virology; HFRS; Human viral diseases; Humans; Infectious diseases; Lassa fever and arenovirus diseases; Medical sciences; Mice; Mice, Inbred Strains; Mutation - drug effects; Nucleosides - chemical synthesis; Nucleosides - metabolism; Nucleosides - pharmacology; Pharmacology. Drug treatments; Ribavirin; Ribavirin - analogs & derivatives; Ribavirin - chemical synthesis; Ribavirin - metabolism; Ribavirin - pharmacology; Rift Valley fever virus; Triazoles - chemical synthesis; Triazoles - metabolism; Triazoles - pharmacology; Tropical viral diseases; Vero Cells; Viral diseases; Rift Valley fever virus; Crimean Congo hemorrhagic fever virus; Andes virus; Hemorrhagic fever with renal syndrome; Hantaan virus HTNV; HFRS; Ribavirin; Hantaan virus; Research and development; Rift valley fever virus; Bunyaviridae; Efficiency; Nucleoside analog; Antiviral; Hemorrhagic fever with renal syndrome,HFRS,Hantaan virus HTNV,Andes virus,Ribavirin,Crimean Congo hemorrhagic fever virus,Rift Valley fever virus; Chemical synthesis; Phlebovirus; Nairovirus; Urinary system disease; Rodentia; Sandfly fever group virus; In vitro; Infection; Virus; In vivo; Vertebrata; Mammalia; Mouse; Viral disease; Animal; Triazole derivatives; Hantavirus; Inosine monophosphate dehydrogenase inhibitor; Crimean-Congo hemorrhagic fever virus
• DOI: 10.1016/j.antiviral.2008.02.003
• ISSN: 0166-3542

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 EC 50 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.