Rottlerin plays an antiviral role at early and late steps of Zika virus infection

Shili Zhou; Quanshi Lin; Changbai Huang; Xiaotong Luo; Xu Tian; Chao Liu; Ping Zhang

doi:10.1016/j.virs.2022.07.012

October 2022

Citation: Shili Zhou, Quanshi Lin, Changbai Huang, Xiaotong Luo, Xu Tian, Chao Liu, Ping Zhang. Rottlerin plays an antiviral role at early and late steps of Zika virus infection .VIROLOGICA SINICA, 2022, 37(5) : 685-694. http://dx.doi.org/10.1016/j.virs.2022.07.012

Rottlerin plays an antiviral role at early and late steps of Zika virus infection

Shili Zhou ^a,b ,
Quanshi Lin ^a,c ,
Changbai Huang ^a,c ,
Xiaotong Luo ^a,d ,
Xu Tian ^a,c ,
Chao Liu ^{a,d
,,} ,
Ping Zhang ^{a,c
,,}

a Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China;
b Medical Research Center, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China;
c Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China;
d Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

Corresponding author: Chao Liu, liuchao9@mail.sysu.edu.cn
Ping Zhang, zhangp36@mail.sysu.edu.cn
Received Date: 12 March 2022
Accepted Date: 26 July 2022
Available online: 05 August 2022

Abstract

Infection of Zika virus (ZIKV) may cause microcephaly and other neurological disorders, while no vaccines and drugs are available. Our study revealed that rottlerin confers a broad antiviral activity against several enveloped viruses, including ZIKV, vesicular stomatitis virus, and herpes simplex virus, but not against two naked viruses (enterovirus 71 and encephalomyocarditis virus). Rottlerin does not have a direct virucidal effect on the virions, and its antiviral effect is independent of its regulation on PKCδ or ATP. Both pretreatment and post-treatment of rottlerin effectively reduce the viral replication of ZIKV. The pretreatment of rottlerin disturbs the endocytosis of enveloped viruses, while the post-treatment of rottlerin acts at a late stage through disturbing the maturation of ZIKV. Importantly, administration of rottlerin in neonatal mice significantly decreased the ZIKV replication in vivo, and alleviated the neurological symptoms caused by ZIKV. Our work suggests that rottlerin exerts an antiviral activity at two distinct steps of viral infection, and can be potentially developed as a prophylactic and therapeutic agent.
- Zika virus (ZIKV)
- , Rottlerin
- , Enveloped virus
- , Replication

Electronic Supplementary Material

10.1016j.virs.2022.07.012-ESM.docx
References
1. Abdelnabi, R., Amrun, S.N., Ng, L.F., Leyssen, P., Neyts, J., Delang, L., 2017. Protein kinases C as potential host targets for the inhibition of chikungunya virus replication. Antivir. Res. 139, 79-87.
2. Chen, F., Shi, Q., Pei, F., Vogt, A., Porritt, R.A., Garcia Jr., G., Gomez, A.C., Cheng, M.H., Schurdak, M.E., Liu, B., Chan, S.Y., Arumugaswami, V., Stern, A.M., Taylor, D.L., Arditi, M., Bahar, I., 2021. A systems-level study reveals host-targeted repurposable drugs against SARS-CoV-2 infection. Mol. Syst. Biol. 17, e10239.
3. Contreras, X., Mzoughi, O., Gaston, F., Peterlin, M.B., Bahraoui, E., 2012. Protein kinase C-delta regulates HIV-1 replication at an early post-entry step in macrophages. Retrovirology 9, 37.
4. Cortese, M., Goellner, S., Acosta, E.G., Neufeldt, C.J., Oleksiuk, O., Lampe, M., Haselmann, U., Funaya, C., Schieber, N., Ronchi, P., Schorb, M., Pruunsild, P., Schwab, Y., Chatel-Chaix, L., Ruggieri, A., Bartenschlager, R., 2017. Ultrastructural characterization of Zika virus replication factories. Cell Rep. 18, 2113-2123.
5. Daikonya, A., Katsuki, S., Wu, J.B., Kitanaka, S., 2002. Anti-allergic agents from natural sources (4):anti-allergic activity of new phloroglucinol derivatives from Mallotus philippensis (Euphorbiaceae). Chem. Pharm. Bull. (Tokyo) 50, 1566-1569.
6. Filone, C.M., Hanna, S.L., Caino, M.C., Bambina, S., Doms, R.W., Cherry, S., 2010. Rift valley fever virus infection of human cells and insect hosts is promoted by protein kinase C epsilon. PLoS One 5, e15483.
7. Grant, A., Ponia, S.S., Tripathi, S., Balasubramaniam, V., Miorin, L., Sourisseau, M., Schwarz, M.C., Sanchez-Seco, M.P., Evans, M.J., Best, S.M., Garcia-Sastre, A., 2016. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19, 882-890.
8. Hamel, R., Dejarnac, O., Wichit, S., Ekchariyawat, P., Neyret, A., Luplertlop, N., PereraLecoin, M., Surasombatpattana, P., Talignani, L., Thomas, F., Cao-Lormeau, V.M., Choumet, V., Briant, L., Despres, P., Amara, A., Yssel, H., Misse, D., 2015. Biology of Zika virus infection in human skin cells. J. Virol. 89, 8880-8896.
9. Ietta, F., Maioli, E., Daveri, E., Gonzaga Oliveira, J., da Silva, R.J., Romagnoli, R., Cresti, L., Maria Avanzati, A., Paulesu, L., Barbosa, B.F., Gomes, A.O., Roberto Mineo, J., Ferro, E.A.V., 2017. Rottlerin-mediated inhibition of Toxoplasma gondii growth in BeWo trophoblast-like cells. Sci. Rep. 7, 1279.
10. Ishii, R., Horie, M., Saito, K., Arisawa, M., Kitanaka, S., 2002. Prostaglandin E(2) production and induction of prostaglandin endoperoxide synthase-2 is inhibited in a murine macrophage-like cell line, RAW 264.7, by Mallotus japonicus phloroglucinol derivatives. Biochim. Biophys. Acta 1571, 115-123.
11. Kang, Y.L., Oh, C., Ahn, S.H., Choi, J.C., Choi, H.Y., Lee, S.W., Choi, I.S., Song, C.S., Lee, J.B., Park, S.Y., 2021. Inhibition of endocytosis of porcine reproductive and respiratory syndrome virus by rottlerin and its potential prophylactic administration in piglets. Antivir. Res. 195, 105191.
12. Kuno, G., Chang, G.J., 2007. Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses. Arch. Virol. 152, 687-696.
13. Lama, Z., Gaudin, Y., Blondel, D., Lagaudriere-Gesbert, C., 2019. Kinase inhibitors tyrphostin 9 and rottlerin block early steps of rabies virus cycle. Antivir. Res. 168, 51-60.
14. Lazear, H.M., Diamond, M.S., 2016. Zika virus:new clinical syndromes and its emergence in the western hemisphere. J. Virol. 90, 4864-4875.
15. Maioli, E., Greci, L., Soucek, K., Hyzdalova, M., Pecorelli, A., Fortino, V., Valacchi, G., 2009. Rottlerin inhibits ROS formation and prevents NFkappaB activation in MCF-7 and HT-29 cells. J. Biomed. Biotechnol. 2009, 742936.
16. Maioli, E., Torricelli, C., Valacchi, G., 2012. Rottlerin and cancer:novel evidence and mechanisms. Sci. World J. 2012, 350826.
17. Mori, N., Ishikawa, C., Senba, M., 2015. Activation of PKC-delta in HTLV-1-infected T cells. Int. J. Oncol. 46, 1609-1618.
18. Mukhopadhyay, S., Kuhn, R.J., Rossmann, M.G., 2005. A structural perspective of the flavivirus life cycle. Nat. Rev. Microbiol. 3, 13-22.
19. Musso, D., Gubler, D.J., 2016. Zika virus. Clin. Microbiol. Rev. 29, 487-524.
20. Oehler, E., Watrin, L., Larre, P., Leparc-Goffart, I., Lastere, S., Valour, F., Baudouin, L., Mallet, H., Musso, D., Ghawche, F., 2014. Zika virus infection complicated by Guillain-Barre syndrome-case report, French Polynesia, December 2013. Euro Surveill. 19, 20720.
21. Ojha, D., Winkler, C.W., Leung, J.M., Woods, T.A., Chen, C.Z., Nair, V., Taylor, K., Yeh, C.D., Tawa, G.J., Larson, C.L., Zheng, W., Haigh, C.L., Peterson, K.E., 2021a. Rottlerin inhibits La Crosse virus-induced encephalitis in mice and blocks release of replicating virus from the Golgi body in neurons. Nat Microbiol 6, 1398-1409.
22. Ojha, D., Woods, T.A., Peterson, K.E., 2021b. Drug-screening strategies for inhibition of virus-induced neuronal cell death. Viruses 13, 2317.
23. Oliphant, T., Engle, M., Nybakken, G.E., Doane, C., Johnson, S., Huang, L., Gorlatov, S., Mehlhop, E., Marri, A., Chung, K.M., Ebel, G.D., Kramer, L.D., Fremont, D.H., Diamond, M.S., 2005. Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat. Med. 11, 522-530.
24. Pandey, S., Chatterjee, A., Jaiswal, S., Kumar, S., Ramachandran, R., Srivastava, K.K., 2016. Protein kinase C-delta inhibitor, Rottlerin inhibits growth and survival of mycobacteria exclusively through Shikimate kinase. Biochem. Biophys. Res. Commun. 478, 721-726.
25. Pierson, T.C., Diamond, M.S., 2018. The emergence of Zika virus and its new clinical syndromes. Nature 560, 573-581.
26. Pierson, T.C., Graham, B.S., 2016. Zika virus:immunity and vaccine development. Cell 167, 625-631.
27. Raghu, H., Sharma-Walia, N., Veettil, M.V., Sadagopan, S., Chandran, B., 2009. Kaposi's sarcoma-associated herpesvirus utilizes an actin polymerization-dependent macropinocytic pathway to enter human dermal microvascular endothelial and human umbilical vein endothelial cells. J. Virol. 83, 4895-4911.
28. Sandgren, K.J., Wilkinson, J., Miranda-Saksena, M., McInerney, G.M., Byth-Wilson, K., Robinson, P.J., Cunningham, A.L., 2010. A differential role for macropinocytosis in mediating entry of the two forms of vaccinia virus into dendritic cells. PLoS Pathog. 6, e1000866.
29. Schuler-Faccini, L., Ribeiro, E.M., Feitosa, I.M., Horovitz, D.D., Cavalcanti, D.P., Pessoa, A., Doriqui, M.J., Neri, J.I., Neto, J.M., Wanderley, H.Y., Cernach, M., ElHusny, A.S., Pone, M.V., Serao, C.L., Sanseverino, M.T., 2015. Brazilian medical genetics society-zika embryopathy task, F., 2016. Possible association between Zika virus infection and microcephaly-Brazil. MMWR Morb. Mortal. Wkly. Rep. 65, 59-62.
30. Shivshankar, P., Lei, L., Wang, J., Zhong, G., 2008. Rottlerin inhibits chlamydial intracellular growth and blocks chlamydial acquisition of sphingolipids from host cells. Appl. Environ. Microbiol. 74, 1243-1249.
31. Stiasny, K., Fritz, R., Pangerl, K., Heinz, F.X., 2011. Molecular mechanisms of flavivirus membrane fusion. Amino Acids 41, 1159-1163.
32. Tapia, J.A., Jensen, R.T., Garcia-Marin, L.J., 2006. Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism. Biochim. Biophys. Acta 1763, 25-38.
33. Torricelli, C., Fortino, V., Capurro, E., Valacchi, G., Pacini, A., Muscettola, M., Soucek, K., Maioli, E., 2008. Rottlerin inhibits the nuclear factor kappaB/cyclin-D1 cascade in MCF-7 breast cancer cells. Life Sci. 82, 638-643.
34. Tsetsarkin, K.A., Kenney, H., Chen, R., Liu, G., Manukyan, H., Whitehead, S.S., Laassri, M., Chumakov, K., Pletnev, A.G., 2016. A full-length infectious cDNA clone of Zika virus from the 2015 epidemic in Brazil as a genetic platform for studies of virushost interactions and vaccine development. mBio 7, e01114-e01116.
35. Valacchi, G., Pecorelli, A., Sticozzi, C., Torricelli, C., Muscettola, M., Aldinucci, C., Maioli, E., 2011. Rottlerin exhibits antiangiogenic effects in vitro. Chem. Biol. Drug Des. 77, 460-470.
36. Wang, B., Thurmond, S., Hai, R., Song, J., 2018. Structure and function of Zika virus NS5 protein:perspectives for drug design. Cell. Mol. Life Sci. 75, 1723-1736.
37. Yu, Y., Deng, Y.Q., Zou, P., Wang, Q., Dai, Y., Yu, F., Du, L., Zhang, N.N., Tian, M., Hao, J.N., Meng, Y., Li, Y., Zhou, X., Fuk-Woo Chan, J., Yuen, K.Y., Qin, C.F., Jiang, S., Lu, L., 2017. A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nat. Commun. 8, 15672.
38. Zheng, F., Li, N., Xu, Y., Zhou, Y., Li, Y.P., 2021. Adaptive mutations promote hepatitis C virus assembly by accelerating core translocation to the endoplasmic reticulum. J. Biol. Chem. 296, 100018.
39. Zhou, S., Yang, C., Zhao, F., Huang, Y., Lin, Y., Huang, C., Ma, X., Du, J., Wang, Y., Long, G., He, J., Liu, C., Zhang, P., 2019. Double-stranded RNA deaminase ADAR1 promotes the Zika virus replication by inhibiting the activation of protein kinase PKR. J. Biol. Chem. 294, 18168-18180.
Proportional views