Potent in vitro activity of beta-D-4 '-chloromethyl-2 '-deoxy-2 '-fluorocytidine against Nipah virus

• Type of Material: Article
• Authors: Michael K Lo, US Centers for Disease Control and Prevention; Franck Amblard, Emory University; Mike Flint, US Centers for Disease Control and Prevention; Payel Chatterjee, US Centers for Disease Control and Prevention; Mahesh Kasthuri, Emory University; Chengwei Li, Emory University; Olivia Russell, Emory University; Kiran Verma, Emory University; Leda Bassit, Emory University; Raymond Schinazi, Emory University; Stuart Nichol, Emory University; Christina F Spiropoulou, US Centers for Disease Control and Prevention
• Language: English
• Date: 2020-03-01
• Publisher: ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Published by Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.antiviral.2020.104712
• Title of Journal or Parent Work: ANTIVIRAL RESEARCH
• Volume: 175
• Start Page: 104712
• End Page: 104712
• Grant/Funding Information: This work was financially supported by CDC Emerging Infectious Disease Research core funding.; This work was also supported in part by CFAR NIH Grant 5P30-AI-50409 (to RFS).
• Keywords: INHIBITOR; RNA; Nipah virus; Nucleoside analog; TOXICITY; Virology; Henipavirus; HENDRA; Pharmacology & Pharmacy; VACCINE; Lumicitabine; CELLS; ALS-8112; RESPIRATORY SYNCYTIAL VIRUS; DISCOVERY; RSV; Science & Technology; Life Sciences & Biomedicine

Abstract

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that continues to cause outbreaks in humans characterized by high mortality and significant clinical sequelae in survivors. Currently, no therapeutics are approved for use in humans against NiV infection. Here, we report that 4ʹ-chloromethyl-2ʹ-deoxy-2ʹ-fluorocytidine (ALS-8112) inhibits NiV. ALS-8112 is the parent nucleoside of lumicitabine, which has been evaluated in phase I and II clinical trials to treat pediatric and adult respiratory syncytial virus infection. In this study, we tested ALS-8112 against NiV and other major human respiratory pneumo- and paramyxoviruses in 2 human lung epithelial cell lines, and demonstrated the ability of ALS-8112 to reduce infectious wild-type NiV yield by over 6 orders of magnitude with no apparent cytotoxicity. However, further cytotoxicity testing in primary cells and bone marrow progenitor cells indicated cytotoxicity at higher concentrations of ALS-8112. Our results warrant the evaluation of lumicitabine against NiV infection in relevant animal models.