Evaluation of kinase inhibitors as potential therapeutics for flavivirus infections.

Publisher: Springer-Verlag Country of Publication: Austria NLM ID: 7506870 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-8798 (Electronic) Linking ISSN: 03048608 NLM ISO Abbreviation: Arch Virol Subsets: MEDLINE

Original Publication: Wien, New York, Springer-Verlag.

Antiviral Agents/*pharmacology ; Flavivirus/*drug effects ; Protein Kinase Inhibitors/*pharmacology; Animals ; Cell Line ; Cell Survival/drug effects ; Chlorocebus aethiops ; Cricetinae ; Flavivirus/classification ; Flavivirus/physiology ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Vero Cells ; Virus Replication/drug effects ; src-Family Kinases/antagonists & inhibitors

The recent introduction of Zika virus (ZIKV), the recurrence of dengue virus (DENV), and the lethality of yellow fever virus (YFV) have had a significant impact on Brazilian society and public health. Here, we targeted two cellular kinases implicated in cell proliferation and cancer that are also important for viral replication: mitogen-activated protein kinase kinase (MEK) and Src. We used two MEK inhibitors - trametinib and selumetinib - and two Src inhibitors - saracatinib and bosutinib - to inhibit ZIKV, DENV, and YFV replication in cell culture. The cytotoxicity of the four inhibitors was determined by the observation of abnormal morphology and quantification of adherent cells by crystal violet staining. The antiviral activity of these drugs was assessed based on the reduction of plaque-forming units in cell culture as evidence of the inhibition of the replication of the selected flaviviruses. All four inhibitors showed antiviral activity, but among them, trametinib was the safest and most efficacious against all of the viruses, inhibiting the replication of ZIKV and YFV by 1000-fold, and DENV2/3 by nearly 100-fold. This pan-antiviral effect shows that trametinib could be repurposed for the treatment of flaviviral infections.

MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2015) Boletim Epidemiológico Reemergência da Febre Amarela Silvestre no Brasil, 2014/2015: situação epidemiológica e a importância da vacinação preventiva e da vigilância intensificada no período sazonal 2015. http://portalarquivos.saude.gov.br/images/pdf/2015/outubro/19/2015-032---FA-ok.pdf . Accessed 26 Aug 2019.
MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2015) Boletim Epidemiológico Monitoramento dos casos de dengue, febre de chikungunya e febre pelo vírus Zika até a Semana Epidemiológica 52, 2015. http://portalarquivos.saude.gov.br/images/pdf/2016/janeiro/15/svs2016-be003-dengue-se52.pdf . Accessed 26 Aug 2019.
MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2016) Boletim Epidemiológico Monitoramento dos casos de dengue, febre de chikungunya e febre pelo vírus Zika até a Semana Epidemiológica 52, 2016. http://portalarquivos.saude.gov.br/images/pdf/2017/abril/06/2017-002-Monitoramento-dos-casos-de-dengue—febre-de-chikungunya-e-febre-pelo-v--rus-Zika-ate-a-Semana-Epidemiologica-52--2016.pdf . Accessed 26 Aug 2019.
MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2017) Boletim Epidemiológico Monitoramento integrado de alterações no crescimento e desenvolvimento relacionadas à infecção pelo vírus Zika e outras etiologias infecciosas, da Semana Epidemiológica 45/2015 até a Semana Epidemiológica 02/2017. http://portalarquivos.saude.gov.br/images/pdf/2017/fevereiro/27/2017_003.pdf . Accessed 26 Aug 2019.
MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2017) Boletim Epidemiológico Emergência epidemiológica de febre amarela no Brasil, no período de dezembro de 2016 a julho de 2017. https://portalarquivos2.saude.gov.br/images/pdf/2017/setembro/06/2017_027.pdf . Accessed 26 Aug 2019.
MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2017) Boletim Epidemiológico Monitoramento dos casos de dengue, febre de chikungunya e febre pelo vírus Zika até a Semana Epidemiológica 52, 2017. https://portalarquivos2.saude.gov.br/images/pdf/2018/janeiro/23/Boletim-2018-001-Dengue.pdf . Accessed 26 Aug 2019.
MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2018) Boletim Epidemiológico Monitoramento integrado de alterações no crescimento e desenvolvimento relacionadas à infecção pelo vírus Zika e outras etiologias infecciosas, até a Semana Epidemiológica 45 de 2018. https://portalarquivos2.saude.gov.br/images/pdf/2018/dezembro/14/2018-061.pdf . Accessed 26 Aug 2019.
MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2018) Boletim Epidemiológico Monitoramento dos casos de dengue, febre de chikungunya e doença aguda pelo vírus Zika até a Semana Epidemiológica 48 de 2018. https://portalarquivos2.saude.gov.br/images/pdf/2018/dezembro/18/2018-064.pdf . Accessed 26 Aug 2019.
MS/SVS—Ministério da Saúde/Secretaria de Vigilância em Saúde (2019) Boletim Epidemiológico Monitoramento dos casos de arboviroses urbanas transmitidas pelo Aedes (dengue, chikungunya e Zika) até a Semana Epidemiológica 12 de 2019 e Levantamento Rápido de Índices para Aedes aegypti (LIRAa). https://portalarquivos2.saude.gov.br/images/pdf/2019/abril/30/2019-013-Monitoramento-dos-casos-de-arboviroses-urbanas-transmitidas-pelo-Aedes-publicacao.pdf . Accessed 26 Aug 2019.
Mittal R, Nguyen D, Debs LH, Patel AP, Liu G, Jhaveri VM, Kay S-I, Mittal J, Bandstra ES, Younis RT, Chapagain P, Jayaweera DT, Liu XZ (2017) Zika virus: an emerging global health threat. Front Cell Infect Microbiol 7:486. (PMID: 10.3389/fcimb.2017.00486)
Brown MT, Cooper JA (1996) Regulation, substrates and functions of src. Biochim Biophys Acta 1287:121–149. (PMID: 8672527)
Bonjardim CA (2017) Viral exploitation of the MEK/ERK pathway—a tale of vaccinia virus and other viruses. Virology 507:267–275. (PMID: 10.1016/j.virol.2016.12.011)
Pagano MA, Tibaldi E, Palù G, Brunati AM (2013) Viral proteins and Src family kinases: mechanisms of pathogenicity from a “liaison dangereuse.” World J Virol 2:71–78. (PMID: 10.5501/wjv.v2.i2.71)
Shum D, Smith JL, Hirsch AJ, Bhinder B, Radu C, Stein DA, Nelson JA, Früh K, Djaballah H (2010) High-content assay to identify inhibitors of dengue virus infection. Assay Drug Dev Technol 8:553–570. (PMID: 10.1089/adt.2010.0321)
Chu JJH, Yang PL (2007) c-Src protein kinase inhibitors block assembly and maturation of dengue virus. Proc Natl Acad Sci USA 104:3520–3525. (PMID: 10.1073/pnas.0611681104)
Oliveira LC, Ribeiro AM, Albarnaz JD, Torres AA, Guimarães LFZ, Pinto AK, Parker S, Doronin K, Brien JD, Buller MR, Bonjardim CA (2020) The small molecule AZD6244 inhibits dengue virus replication in vitro and protects against lethal challenge in a mouse model. Arch Virol 165:671–681. (PMID: 10.1007/s00705-020-04524-7)
Albarnaz JD, De OLC, Torres AA, Palhares RM, Casteluber MC, Rodrigues CM, Cardozo PL, De SAMRR, Pacca CC, Ferreira PCP, Kroon EG, Nogueira ML, Bonjardim CA (2014) MEK/ERK activation plays a decisive role in yellow fever virus replication: implication as an antiviral therapeutic target. Antiviral Res 111:82–92. (PMID: 10.1016/j.antiviral.2014.09.004)
Śliwka L, Wiktorska K, Suchocki P, Milczarek M, Mielczarek S, Lubelska K, Cierpiał T, Łyzwa P, Kiełbasiński P, Jaromin A, Flis A, Chilmonczyk Z (2016) The comparison of MTT and CVS assays for the assessment of anticancer agent interactions. PLoS ONE 11:e0155772. (PMID: 10.1371/journal.pone.0155772)
Donald CL, Brennan B, Cumberworth SL, Rezelj VV, Clark JJ, Cordeiro MT, de Oliveira F, França R, Pena LJ, Wilkie GS, Da Silva Filipe A, Davis C, Hughes J, Varjak M, Selinger M, Zuvanov L, Owsianka AM, Patel AH, McLauchlan J, Lindenbach BD, Fall G, Sall AA, Biek R, Rehwinkel J, Schnettler E, Kohl A (2016) Full genome sequence and sfRNA interferon antagonist activity of Zika virus from Recife, Brazil. PLoS Negl Trop Dis 10:e0005048. (PMID: 10.1371/journal.pntd.0005048)
Figueiredo LB, Sakamoto T, Leomil Coelho LF, De Oliveira Rocha ES, Gomes Cota MM, Portela Ferreira G, De Oliveira JG, Kroon EG (2014) Dengue virus 2 American-Asian genotype identified during the 2006/2007 outbreak in Piauí, Brazil reveals a Caribbean route of introduction and dissemination of dengue virus in Brazil. PLoS ONE 9:e104516. (PMID: 10.1371/journal.pone.0104516)
Figueiredo LB, Cecílio AB, Ferreira GP, Drumond BP, De OJG, Bonjardim CA, Ferreira PCP, Kroon EG (2008) Dengue virus 3 genotype 1 associated with dengue fever and dengue hemorrhagic fever, Brazil. Emerg Infect Dis 14:314–316. (PMID: 10.3201/eid1402.070278)
Marchevsky RS, da Luz Leal M, Homma A, Coutinho ESF, Camacho LAB, Jabor AV, Galler R, Freire MS (2006) Molecular and phenotypic analysis of a working seed lot of yellow fever virus 17DD vaccine strain produced from the secondary seed lot 102/84 with an additional passage in chicken embryos. Biologicals 34:191–197. (PMID: 10.1016/j.biologicals.2005.09.005)
Dochi T, Akita A, Kishimoto N, Takamune N, Misumi S (2017) Trametinib suppresses HIV-1 replication by interfering with the disassembly of human immunodeficiency virus type 1 capsid core. Biochem Biophys Res Commun 495:1846–1850. (PMID: 10.1016/j.bbrc.2017.11.177)
Schräder T, Dudek SE, Schreiber A, Ehrhardt C, Planz O, Ludwig S (2018) The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression. Antiviral Res 157:80–92. (PMID: 10.1016/j.antiviral.2018.07.006)
Menzel N, Fischl W, Hueging K, Bankwitz D, Frentzen A, Haid S, Gentzsch J, Kaderali L, Bartenschlager R, Pietschmann T (2012) MAP-kinase regulated cytosolic phospholipase A2 activity is essential for production of infectious hepatitis C virus particles. PLoS Pathog 8:e1002829. (PMID: 10.1371/journal.ppat.1002829)
Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, Tcw J, Kouznetsova J, Ogden SC, Hammack C, Jacob F, Nguyen HN, Itkin M, Hanna C, Shinn P, Allen C, Michael SG, Simeonov A, Huang W, Christian KM, Goate A, Brennand KJ, Huang R, Xia M, Ming GL, Zheng W, Song H, Tang H (2016) Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med 22:1101–1107. (PMID: 10.1038/nm.4184)
Yamaguchi T, Kakefuda R, Tajima N, Sowa Y, Sakai T (2011) Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int J Oncol 39:23–31. (PMID: 21523318)
Fagone P, Ciurleo R, Lombardo SD, Iacobello C, Palermo CI, Shoenfeld Y, Bendtzen K, Bramanti P, Nicoletti F (2020) Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies. Autoimmun Rev 19:102571. (PMID: 10.1016/j.autrev.2020.102571)
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JMG, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114. (PMID: 10.1056/NEJMoa1203421)

CBB - AUC-00071-15, CBB - APQ-01670-11 FAPEMIG Fundação de Apoio a Pesquisa do Estado de Minas Gerais (BR); CBB - APQ -04178-17 FAPEMIG/PPSUS Pesquisa Para o Serviço Único de Saúde (BR)

0 (Antiviral Agents)
0 (Protein Kinase Inhibitors)
EC 2.7.10.2 (src-Family Kinases)
EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)

Date Created: 20210308 Date Completed: 20210419 Latest Revision: 20210419

20231215

PMC7938686

10.1007/s00705-021-05021-1

33683474