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Protection Against Filovirus Diseases by a Novel Broad-Spectrum Nucleoside Analogue BCX4430

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Protection Against Filovirus Diseases by a Novel Broad-Spectrum Nucleoside Analogue BCX4430 LETTER doi:10.1038/nature13027 Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430 Travis K. Warren1, Jay Wells1, Rekha G. Panchal1, Kelly S. Stuthman1, Nicole L. Garza1, Sean A. Van Tongeren1, Lian Dong1, Cary J. Retterer1, Brett P. Eaton1, Gianluca Pegoraro1, Shelley Honnold1, Shanta Bantia2, Pravin Kotian2, Xilin Chen2, Brian R. Taubenheim2{, Lisa S. Welch1, Dena M. Minning3, Yarlagadda S. Babu2, William P. Sheridan2 & Sina Bavari1 Filoviruses are emerging pathogens and causative agents of viral multiple filoviruses would provide a key, cost-effective component of haemorrhagic fever. Case fatality rates of filovirus disease outbreaks public-health preparedness plans in outbreak-prone regions. are among the highest reported for any human pathogen, exceeding The broad-spectrum antiviral agent ribavirin, a trizole nucleoside 90% (ref. 1). Licensed therapeutic or vaccine products are not avail- effective against multiple pathogenic RNA viruses, is not active against able to treat filovirus diseases. Candidate therapeutics previously filoviruses11. Other small molecules—including the adenosine analogue shown to be efficacious in non-human primate disease models are 3-deazaneplanocin A (c3-Npc A) and T-705 (favipiravir), a substituted based on virus-specific designs and have limited broad-spectrum anti- pyrazine compound —have conferred a high-degree of protection against viral potential. Here we show that BCX4430, a novel synthetic aden- filoviruses in rodents but have not been reported to protect non-human osine analogue, inhibits infection of distinct filoviruses in human primates12–18. cells. Biochemical, reporter-based and primer-extension assays indi- BCX4430, a novel nucleoside analogue (Fig. 1a), was synthesized (Sup- cate that BCX4430 inhibits viral RNA polymerase function, acting plementary Information) as part of a small-molecule library designed as a non-obligate RNA chain terminator. Post-exposure intramuscular as inhibitors of viral RNA polymerase activity. BCX4430 is designed to administration of BCX4430 protects against Ebola virus and Marburg inhibit viral RNA polymerase activity indirectly through non-obligate virus disease in rodent models. Most importantly, BCX4430 com- RNA chain termination, a mechanism requiring anabolism of the par- pletely protects cynomolgus macaques from Marburg virus infection ent compound to BCX4430-triphosphate (BCX4430-TP). Then, after when administered as late as 48 hours after infection. In addition, pyrophosphate cleavage, incorporation of BCX4430-monophosphate BCX4430 exhibits broad-spectrum antiviral activity against numer- (BCX4430-MP) into nascent viral RNA strands would be expected to ous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, cause premature termination of transcription and replication of viral coronaviruses and flaviviruses. This is the first report, to our know- RNA. In support of this proposed mechanism, BCX4430 is rapidly phos- ledge, of non-human primate protection from filovirus disease by a phorylated to BCX4430-TP in cultured cell lines and primary hepato- synthetic drug-like small molecule. We provide additional pharmaco- cytes, similar to the natural adenosine nucleoside (Fig. 1b and Extended logical characterizations supporting the potential development of Data Fig. 1a). Addition of BCX4430 reduces expression of green fluo- BCX4430 as a countermeasure against human filovirus diseases and rescent protein (GFP) in an artificial EBOV minigenome replicon assay other viral diseases representing major public health threats. (Fig. 1c and Extended Data Fig. 1b), in which virion structural proteins Members of the family Filoviridae include Ebola virus (EBOV), Mar- comprising the viral ribonucleoprotein complex mediate transcription burg virus (MARV), Ravn virus (RAVV), Sudan virus (SUDV) and Bun- and replication of anRNA replicon template containing a GFP-reporter dibugyo virus (BDBV), all of which cause severe viral haemorrhagic fevers cassette. BCX4430-TP inhibits hepatitis C virus (HCV) RNA polymer- in humans. In nature, filoviruses are transmitted by physical contact between infected individuals, presumably via infected bodily fluids2. ase transcriptional activity in a cell-free, isolated enzyme transcription Initial filovirus disease manifestations include fever, headache, vom- assay (Fig. 1d) (an isolated filovirus RNA polymerase enzyme assay has iting and diarrhoea3. Fatal cases are characterized by viraemia, elevated yet to be reported) and induces premature termination of RNA chain liver-associated enzyme levels, coagulopathy and haemorrhage. Filovirus synthesis by HCV RNA polymerase during template-directed primer- disease outbreaks occur sporadically, most frequently in sub-Saharan extension assays (Fig. 1e and Extended Data Fig. 1c). In virus-infected Africa, with reported case fatality rates exceeding 90% (ref. 1). In 2012, cells, BCX4430 reduces surface-expressed MARV and EBOV glycopro- simultaneous outbreaks involved MARV, SUDV and BDBV, an emer- teinand reduces the production ofintracellular and extracellular MARV gent filovirus isolated in 20074. The historical occurrence of indepen- RNA (Fig. 1f–h and Extended Data Fig. 1d). Additionally, HeLa cells dent and simultaneous emergence of distinct filoviruses highlights the incubated with $25 mM BCX4430 produce no detectable infectious need for the identification and development of an efficacious broad- MARV virus (concentration providing 90% inhibition (IC90) 5 5.4 mM) spectrum antiviral product. (Fig. 1h). Although no licensed antiviral preventative or therapeutic agents are Taken together, these assessments strongly support our hypothesis currently available to combat filovirus disease in humans, a number of that BCX4430 inhibits viral RNA polymerase function by inducing RNA candidates are being developed and have been evaluated in non-human chain termination. Findings from primer-extension reactions suggest primate filovirus disease models. These models closely reproduce the that termination occurs two bases after incorporation of BCX4430- known clinical and pathophysiological aspects of fatal human infec- MP, perhaps as a result of inhibitory stereochemical distortions of the tion. Nucleic-acid-based products, antibody therapies and therapeutic nascent RNA chain. We observed no evidence of BCX4430-MP incor- vaccines have successfully protected non-human primates from filo- poration into human RNA or DNA on exposing human Huh-7 cells to 5–10 virus disease , but these approaches rely on virus-specific designs that concentrations of BCX4430 exceeding the MARV IC50 by more than inherently limit the spectrum of activity and potential utility of individual tenfold (Extended Data Fig. 1f). The basis of the selectivity of BCX4430 treatments. The development of a single therapeutic agent active against for viral polymerases is not yet known. 1Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA. 2BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA. 3MedExpert Consulting, Inc., Indialantic, Florida 32903, USA. {Present address: Wilco Consulting, LLC, Durham, North Carolina 27712, USA. 402 | NATURE | VOL 508 | 17 APRIL 2014 ©2014 Macmillan Publishers Limited. All rights reserved LETTER RESEARCH ab c d NH2 3,500 1.2 1.2 3 140 BCX4430 H BCX4430 Relative GFP-positive cells H (2S,3S,4R,5R)-2-(4-amino- N 3H adenosine 1.0 1.0 120 5H-pyrrolo[3,2-d]pyrimidin- N 7-yl)-5-(hydroxymethyl) cells) 2,500 100 pyrrolidine-3,4-diol 6 0.8 0.8 N 80 HO 0.6 0.6 H 1,500 60 N 0.4 0.4 40 Relative cell number 500 0.2 0.2 20 OH OH Relative transcriptional activity Solubility (H O, deionized): >150 mg ml–1 Analyte (pmol per 10 0 0 0 2 0 0 1 3 103060 25 50 Molecular weight: 265.3 DP TP DP TP DP TP DP TP 0.78 1.56 3.13 6.25 12.5 μ No L BCX4430-TP ( M) LogP: –0.99 10 μM 30 μM 10 μM 30 μM BCX4430 (μM) e 32P-5′-GG f g BCX1777 50 h 3 ′-CCGUAGUUAUUAAUAUGUA-5′ 100 100 Medium only 1: Control 2: CTP 3: CTP, ATP 4: CTP, 3′-dATP, Viral RNA 21 nt MARV 50 5: CTP, BCX4430-TP Infectious 50 EBOV 14 nt 6: CTP, ATP, UTP virus 7: CTP, 3′-dATP, 12.5 μM BCX4430 UTP, ATP 8: CTP, BCX4430-TP, Percentage inhibition Percentage inhibition UTP, ATP 0 M: Markers 0 12 2 nt 0 012 BCX4430 concentration μ μ 12345678M BCX4430 concentration log10( M) log10( M) Figure 1 | Pharmacological characterization of BCX4430. a, BCX4430 template-directed primer (32P-59-GG) extension assay. nt, nucleotides. chemical structure and properties. LogP, log of partition coefficient. f, Expression of EBOV and MARV glycoprotein in infected HeLa cells b, Conversion of 3H-BCX4430 or 3H-adenosine to diphosphate (DP) or (n 5 5–6). g, MARV-infected HeLa cells. Green, a-MARV glycoprotein; triphosphate (TP) forms in Huh-7 cells (n 5 1). c, Effect of BCX4430 on blue, Hoechst dye. Scale bar, 100 mm. h, Production of intracellular MARV replication of an EBOV minigenome RNA replicon in cultured cells (n 5 6). RNA (n 5 4) and infectious virus in MARV-infected HeLa cells (n 5 2 No L, L-polymerase encoding plasmid omitted from reaction. d, BCX4430-TP technical replicates). Data in c, d, and h are expressed as mean 1 standard suppresses HCV NS5B (NS5B-1b-D21) RNA polymerase activity (n 5 2). deviation (s.d.). Data in f are expressed as mean 1 standard error of the e, RNA products synthesized by purified HCV polymerase, in a mean (s.e.m.). To assess the spectrum of antiviral activity of BCX4430,
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