[KSCI] Korea Science Citation Index Service

http://dx.doi.org/10.5483/BMBRep.2020.53.3.175

Antiviral activity of sertindole, raloxifene and ibutamoren against transcription and replication-competent Ebola virus-like particles

Yoon, Yi-Seul (Virus Research Group, Korea Research Institute of Chemical Technology (KRICT))
Jang, Yejin (Virus Research Group, Korea Research Institute of Chemical Technology (KRICT))
Hoenen, Thomas (Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institute)
Shin, Heegwon (Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST))
Lee, Younghoon (Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST))
Kim, Meehyein (Virus Research Group, Korea Research Institute of Chemical Technology (KRICT))

Publication Information

BMB Reports / v.53, no.3, 2020 , pp. 166-171 More about this Journal

Abstract

A chemical library comprising 2,354 drug-like compounds was screened using a transcription and replication-competent viruslike particle (trVLP) system implementing the whole Ebola virus (EBOV) life cycle. Dose-dependent inhibition of Ebola trVLP replication was induced by 15 hit compounds, which primarily target different types of G protein-coupled receptors (GPCRs). Based on the chemical structure, the compounds were divided into three groups, diphenylmethane derivatives, promazine derivatives and chemicals with no conserved skeletons. The third group included sertindole, raloxifene, and ibutamoren showing prominent antiviral effects in cells. They downregulated the expression of viral proteins, including the VP40 matrix protein and the envelope glycoprotein. They also reduced the amount of EBOV-derived tetracistronic minigenome RNA incorporated into progeny trVLPs in the culture supernatant. Particularly, ibutamoren, which is a known agonist of growth hormone secretagogue receptor (GHSR), showed the most promising antiviral activity with a 50% effective concentration of 0.2 μM, a 50% cytotoxic concentration of 42.4 μM, and a selectivity index of 222.8. Here, we suggest a strategy for development of anti-EBOV therapeutics by adopting GHSR agonists as hit compounds.

Keywords

Antiviral; Ebola virus; Ibutamoren; Raloxifene; Sertindole;

Citations & Related Records

Reference

1	Kuhn JH, Becker S, Ebihara H et al (2010) Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Arch Virol 155, 2083-2103 DOI
2	Jun SR, Leuze MR, Nookaew I et al (2015) Ebolavirus comparative genomics. FEMS Microbiol Rev 39, 764-778 DOI
3	Schumann M, Gantke T and Muhlberger E (2009) Ebola virus VP35 antagonizes PKR activity through its C-terminal interferon inhibitory domain. J Virol 83, 8993-8997 DOI
4	McCarthy SE, Johnson RF, Zhang YA, Sunyer JO and Harty RN (2007) Role for amino acids 212KLR214 of Ebola virus VP40 in assembly and budding. J Virol 81, 11452-11460 DOI
5	Biedenkopf N, Schlereth J, Grunweller A, Becker S and Hartmann RK (2016) RNA Binding of Ebola Virus VP30 Is Essential for Activating Viral Transcription. J Virol 90, 7481-7496 DOI
6	Banadyga L, Hoenen T, Ambroggio X, Dunham E, Groseth A and Ebihara H (2017) Ebola virus VP24 interacts with NP to facilitate nucleocapsid assembly and genome packaging. Sci Rep 7, 7698 DOI
7	Carette JE, Raaben M, Wong AC et al (2011) Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature 477, 340-343 DOI
8	Kondratowicz AS, Lennemann NJ, Sinn PL et al (2011) T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for zaire ebolavirus and lake victoria marburgvirus. Proc Natl Acad Sci U S A 108, 8426-8431 DOI
9	Sugita Y, Matsunami H, Kawaoka Y, Noda T and Wolf M (2018) Cryo-EM structure of the Ebola virus nucleoprotein-RNA complex at 3.6 A resolution. Nature 563, 137-140 DOI
10	Jasenosky LD, Neumann G, Lukashevich I and Kawaoka Y (2001) Ebola virus VP40-induced particle formation and association with the lipid bilayer. J Virol 75, 5205-5214 DOI
11	Wang Y, Cui R, Li G et al (2016) Teicoplanin inhibits Ebola pseudovirus infection in cell culture. Antiviral Res 125, 1-7 DOI
12	Cohen NJ, Brown CM, Alvarado-Ramy F et al (2016) Travel and border health measures to prevent the international spread of Ebola. MMWR Suppl 65, 57-67
13	Edwards MR, Pietzsch C, Vausselin T, Shaw ML, Bukreyev A and Basler CF (2015) High-Throughput Minigenome System for Identifying Small-Molecule Inhibitors of Ebola Virus Replication. ACS Infect Dis 1, 380-387 DOI
14	Kouznetsova J, Sun W, Martinez-Romero C et al (2014) Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg Microbes Infect 3, e84
15	Welch SR, Guerrero LW, Chakrabarti AK et al (2016) Lassa and Ebola virus inhibitors identified using minigenome and recombinant virus reporter systems. Antiviral Res 136, 9-18 DOI
16	Arie S (2018) Ebola: WHO expresses "very serious concern" about Congo outbreak. BMJ 363, k4430 DOI
17	Hoenen T, Watt A, Mora A and Feldmann H (2014) Modeling the lifecycle of Ebola virus under biosafety level 2 conditions with virus-like particles containing tetracistronic minigenomes. J Vis Exp, 52381
18	Nevozhay D (2014) Cheburator software for automatically calculating drug inhibitory concentrations from in vitro screening assays. PLoS One 9, e106186 DOI
19	Lee N, Shum D, Konig A et al (2018) High-throughput drug screening using the Ebola virus transcription- and replication-competent virus-like particle system. Antiviral Res 158, 226-237 DOI
20	Fan H, Du X, Zhang J et al (2017) Selective inhibition of Ebola entry with selective estrogen receptor modulators by disrupting the endolysosomal calcium. Sci Rep 7, 41226 DOI
21	Kim J, Shin JS, Ahn S, Han SB and Jung YS (2018) 3-Aryl-1,2,4-oxadiazole derivatives active against human rhinovirus. ACS Med Chem Lett 9, 667-672 DOI
22	Cheng H, Lear-Rooney CM, Johansen L et al (2015) Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists. J Virol 89, 9932-9938 DOI
23	Watt A, Moukambi F, Banadyga L et al (2014) A novel life cycle modeling system for Ebola virus shows a genome length-dependent role of VP24 in virus infectivity. J Virol 88, 10511-10524 DOI
24	Thorne N, Shen M, Lea WA et al (2012) Firefly luciferase in chemical biology: a compendium of inhibitors, mechanistic evaluation of chemotypes, and suggested use as a reporter. Chem Biol 19, 1060-1072 DOI
25	Atwood BK, Lopez J, Wager-Miller J, Mackie K and Straiker A (2011) Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis. BMC Genomics 12, 14 DOI
26	Jung E, Nam S, Oh H et al (2019) Neutralization of acidic intracellular vesicles by niclosamide inhibits multiple steps of the dengue virus life cycle in vitro. Sci Rep 9, 8682 DOI
27	Jang Y, Shin JS, Yoon YS et al (2018) Salinomycin inhibits influenza virus infection by disrupting endosomal acidification and viral matrix protein 2 function. J Virol 92, e01441-18
28	Svensson J, Lonn L, Jansson JO et al (1998) Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab 83, 362-369 DOI
29	Patchett AA, Nargund RP, Tata JR et al (1995) Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci U S A 92, 7001-7005 DOI
30	Borroto-Escuela DO, Brito I, Romero-Fernandez W et al (2014) The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components. Int J Mol Sci 15, 8570-8590 DOI