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Review
. 2016 May-Jun;9(3):220-6.
doi: 10.1016/j.jiph.2016.04.002. Epub 2016 Apr 16.

BCX4430 - A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease

Raymond Taylor  1 , Pravin Kotian  2 , Travis Warren  3 , Rekha Panchal  3 , Sina Bavari  3 , Justin Julander  4 , Sylvia Dobo  2 , Angela Rose  2 , Yahya El-Kattan  2 , Brian Taubenheim  5 , Yarlagadda Babu  2 , William P Sheridan  6
Affiliations
Review

BCX4430 - A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease

Raymond Taylor et al. J Infect Public Health. 2016 May-Jun.

Abstract

The adenosine nucleoside analog BCX4430 is a direct-acting antiviral drug under investigation for the treatment of serious and life-threatening infections from highly pathogenic viruses, such as the Ebola virus. Cellular kinases phosphorylate BCX4430 to a triphosphate that mimics ATP; viral RNA polymerases incorporate the drug's monophosphate nucleotide into the growing RNA chain, causing premature chain termination. BCX4430 is active in vitro against many RNA viral pathogens, including the filoviruses and emerging infectious agents such as MERS-CoV and SARS-CoV. In vivo, BCX4430 is active after intramuscular, intraperitoneal, and oral administration in a variety of experimental infections. In nonclinical studies involving lethal infections with Ebola virus, Marburg virus, Rift Valley fever virus, and Yellow Fever virus, BCX4430 has demonstrated pronounced efficacy. In experiments conducted in several models, both a reduction in the viral load and an improvement in survival were found to be related to the dose of BCX4430. A Phase 1 clinical trial of intramuscular administration of BCX4430 in healthy subjects is currently ongoing.

Keywords: BCX4430; Ebola virus disease; MERS-CoV; Marburg virus disease; Nucleoside analog; Yellow Fever.

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Figures

Figure 1
Figure 1
Anabolism of BCX4430 to BCX4430-TP (BCX6870) in hepatocytes in vitro (left panel) and levels of BCX4430 in the plasma and BCX4430-TP in the liver of rats after an IM injection of BCX4430 (right panel). Redrawn from . Cells were incubated with 10 μM BCX4430 for the indicated times, and the levels of BCX4430-TP were quantitated by HPLC; the plasma samples were obtained and the livers were harvested from rats following administration of a 30 mg/kg BCX4430 dose by intramuscular injection, and the plasma BCX4430 and the liver BCX4430-TP were quantitated by HPLC/tandem MS.
Figure 2
Figure 2
Structure of BCX4430 (left panel), an adenosine nucleoside analog broad-spectrum antiviral drug, and its active nucleotide form, BCX4430-triphosphate (also designated as BCX6870) (right panel).
Figure 3
Figure 3
Non-obligate chain termination of hepatitis C through RNA-dependent, template-directed RNA synthesis by incubation with BCX4430 triphosphate (BCX6870) in vitro. Chain termination as a result of incorporation of BCX4430 is shown in lanes 5 and 8. Lanes 4 and 7 show 3′-deoxyATP, a known obligate chain terminator positive control. Lane 6 shows the pattern of RNA oligomers made with no inhibitors present or normal nucleotides present.
Figure 4
Figure 4
Variation in and low efficiency of conversion of BCX4430 to BCX4430-TP in cell lines commonly used for in vitro evaluation of antiviral activity of test agents; the data shown indicate mean and SD. Redrawn from ; right-hand scale indicates the percent of BCX4430-TP mean levels observed at 24 h in fresh human hepatocytes. The cell lines were incubated with 10 μM BCX4430 for the indicated times, and the levels of BCX4430-TP were quantitated by HPLC.
Figure 5
Figure 5
Concentration–response results for the inhibition of virus proliferation in cell culture assays using a Vero-E6 cell line infected with MERS-CoV (Jordan N3 strain) (left panel) and the Yellow Fever Virus (YFV, 17D strain) (right panel).
Figure 6
Figure 6
Relationship between the dose of BCX4430 to the antiviral effect (left panel) and survival (right panel) in Syrian golden hamsters inoculated with the Yellow Fever virus. The left panel open symbols shows data for each animal (n = 10 per dose group), and the horizontal bars shows the geometric mean for each dose group; the inset shows the best-fit nonlinear regression of BCX4430 dose with viral load (GraphPad Prism v6.07), indicating a typical and steep concentration–inhibition relationship. The right panel closed symbols show the proportion of animals surviving at each dose level in the same experiment, with error bars indicating the exact binomial confidence intervals. The line shows the best-fit logistic regression of dose with proportion surviving (XLSTAT Version 2015.5.01.23039).
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