Recent progress and challenges in drug development to fight hand, foot and mouth disease

References

• Yi EJ, Shin YJ, Kim JH, et al. Enterovirus 71 infection and vaccines. Clin Exp Vaccine Res. 2017 Jan;6(1):4–14.
   PubMed Web of Science ®Google Scholar
• Singh S, Poh CL, Chow VT. Complete sequence analyses of enterovirus 71 strains from fatal and non-fatal cases of the hand, foot and mouth disease outbreak in Singapore (2000). Microbiol Immunol. 2002;46(11):801–808.
   PubMed Web of Science ®Google Scholar
• Chang PC, Chen SC, Chen KT. The current status of the disease caused by enterovirus 71 infections: epidemiology, pathogenesis, molecular epidemiology, and vaccine development. Int J Environ Res Public Health. 2016 Sep 9;13(9):pii: E890.
   Web of Science ®Google Scholar
• Solomon T, Lewthwaite P, Perera D, et al. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 2010 Nov;10(11):778–790.
   PubMed Web of Science ®Google Scholar
• Cox JA, Hiscox JA, Solomon T, et al. Immunopathogenesis and virus–host interactions of enterovirus 71 in patients with hand, foot and mouth disease. Front Microbiol. 2017 cited 2017 Nov 28;8(2249).
   Google Scholar
• Thompson SR, Sarnow P. Enterovirus 71 contains a type I IRES element that functions when eukaryotic initiation factor eIF4G is cleaved. Virology. 2003 Oct 10;315(1):259–266.
   PubMed Web of Science ®Google Scholar
• Kok CC, Phuektes P, Bek E, et al. Modification of the untranslated regions of human enterovirus 71 impairs growth in a cell-specific manner. J Virol. 2012 Jan;86(1):542–552.
   PubMed Web of Science ®Google Scholar
• Yuan J, Shen L, Wu J, et al. Enterovirus A71 proteins: structure and function. Front Microbiol. 2018;9:286.
   PubMed Web of Science ®Google Scholar
• Wang X, Peng W, Ren J, et al. A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71. Nat Struct Mol Biol. 2012 Mar 4;19(4):424–429.
   PubMed Web of Science ®Google Scholar
• Dang M, Wang X, Wang Q, et al. Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71. Protein Cell. 2014 Sep;5(9):692–703.
   PubMed Web of Science ®Google Scholar
• Cong H, Du N, Yang Y, et al. Enterovirus 71 2b induces cell apoptosis by directly inducing the conformational activation of the proapoptotic protein bax. J Virol. 2016 Nov 1;90(21):9862–9877.
   PubMed Web of Science ®Google Scholar
• Xiao X, Lei X, Zhang Z, et al. Enterovirus 3A facilitates viral replication by promoting phosphatidylinositol 4-kinase iiibeta-ACBD3 interaction. J Virol. 2017 Oct 1; 91: 19.
   Web of Science ®Google Scholar
• Sun D, Chen S, Cheng A, et al. Roles of the picornaviral 3C proteinase in the viral life cycle and host cells. Viruses. 2016 Mar 17;8(3):82.
   PubMed Web of Science ®Google Scholar
• Sun Y, Wang Y, Shan C, et al. Enterovirus 71 VPg uridylation uses a two-molecular mechanism of 3D polymerase. J Virol. 2012 Dec;86(24):13662–13671.
   PubMed Web of Science ®Google Scholar
• Lin JY, Shih SR. Cell and tissue tropism of enterovirus 71 and other enteroviruses infections. J Biomed Sci. 2014 Mar 7;21:18.
   PubMed Web of Science ®Google Scholar
• Chen CS, Yao YC, Lin SC, et al. Retrograde axonal transport: a major transmission route of enterovirus 71 in mice. J Virol. 2007 Sep;81(17):8996–9003.
   PubMed Web of Science ®Google Scholar
• Khong WX, Yan B, Yeo H, et al. A non-mouse-adapted enterovirus 71 (EV71) strain exhibits neurotropism, causing neurological manifestations in a novel mouse model of EV71 infection. J Virol. 2012 Feb;86(4):2121–2131.
   PubMed Web of Science ®Google Scholar
• Jia CS, Liu JN, Li WB, et al. The cross-reactivity of the enterovirus 71 to human brain tissue and identification of the cross-reactivity related fragments. Virol J. 2010 Feb 22;7:47.
   PubMed Web of Science ®Google Scholar
• Chua BH, Phuektes P, Sanders SA, et al. The molecular basis of mouse adaptation by human enterovirus 71. J Gen Virol. 2008 Jul;89(Pt(7)):1622–1632.
   Google Scholar
• Feuer R, Mena I, Pagarigan RR, et al. Coxsackievirus B3 and the neonatal CNS: the roles of stem cells, developing neurons, and apoptosis in infection, viral dissemination, and disease. Am J Pathol. 2003 Oct;163(4):1379–1393.
   PubMed Web of Science ®Google Scholar
• Tabor-Godwin JM, Ruller CM, Bagalso N, et al. A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS. J Neurosci. 2010 Jun 23;30(25):8676–8691.
   PubMed Web of Science ®Google Scholar
• Li R, Liu L, Mo Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med. 2014 Feb 27;370(9):829–837.
   PubMed Web of Science ®Google Scholar
• Zhu F, Xu W, Xia J, et al. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N Engl J Med. 2014 Feb 27;370(9):818–828.
   PubMed Web of Science ®Google Scholar
• Wei M, Meng F, Wang S, et al. 2-Year efficacy, immunogenicity, and safety of vigoo enterovirus 71 vaccine in healthy chinese children: a randomized open-label study. J Infect Dis. 2017 Jan 1;215(1):56–63.
   PubMed Web of Science ®Google Scholar
• Zhang W, Dai W, Zhang C, et al. A virus-like particle-based tetravalent vaccine for hand, foot, and mouth disease elicits broad and balanced protective immunity. Emerg Microbes Infect. 2018 May 18;7(1):94.
   PubMed Web of Science ®Google Scholar
• Yang Z, Gao F, Wang X, et al. Development and characterization of an enterovirus 71 (EV71) virus-like particles (VLPs) vaccine produced in Pichia pastoris. Hum Vaccin Immunother. 2019 Aug 15:1–9. Epub ahead of print. DOI:10.1080/21645515.2019.1649554.
   Web of Science ®Google Scholar
• Pallansch MA. Ending use of oral poliovirus vaccine – a difficult move in the polio endgame. N Engl J Med. 2018 Aug 30;379(9):801–803.
   PubMed Web of Science ®Google Scholar
• Jia Q, Ng Q, Chin W, et al. Effective in vivo therapeutic IgG antibody against VP3 of enterovirus 71 with receptor-competing activity. Sci Rep. 2017 Apr 19;7:46402.
   PubMed Web of Science ®Google Scholar
• Lin T, Xianyu L, Lyu S. Monoclonal neutralizing antibodies against EV71 screened from mice immunized with yeast-produced virus-like particles. Virol Sin. 2015 Jun;30(3):208–213.
   PubMed Web of Science ®Google Scholar
• Lin H, Huang L, Zhou J, et al. Efficacy and safety of interferon-alpha2b spray in the treatment of hand, foot, and mouth disease: a multicenter, randomized, double-blind trial. Arch Virol. 2016 Nov;161(11):3073–3080.
   PubMed Web of Science ®Google Scholar
• Huang X, Zhang X, Wang F, et al. Clinical efficacy of therapy with recombinant human interferon alpha1b in hand, foot, and mouth disease with enterovirus 71 infection. PLoS One. 2016;11(2):e0148907.
   PubMed Web of Science ®Google Scholar
• Khong WX, Foo DG, Trasti SL, et al. Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model. J Virol. 2011 Apr;85(7):3067–3076.
   PubMed Web of Science ®Google Scholar
• Jiao W, Tan SR, Huang YF, et al. The effectiveness of different doses of intravenous immunoglobulin on severe hand, foot and mouth disease: a meta-analysis. Med Princ Pract. 2019 Jan 15.
   PubMed Web of Science ®Google Scholar
• Wang SM, Lei HY, Huang MC, et al. Therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema. Pediatr Pulmonol. 2005 Mar;39(3):219–223.
   PubMed Web of Science ®Google Scholar
• Chi CY, Khanh TH, Thoa le PK, et al. Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. Crit Care Med. 2013 Jul;41(7):1754–1760.
   PubMed Web of Science ®Google Scholar
• Wang SM. Milrinone in enterovirus 71 brain stem encephalitis. Front Pharmacol. 2016;7:82.
   PubMed Web of Science ®Google Scholar
• Shih S-R, Tsai M-C, Tseng S-N, et al. Mutation in enterovirus 71 capsid protein VP1 confers resistance to the inhibitory effects of pyridyl imidazolidinone. Antimicrob Agents Chemother. 2004;48(9):3523–3529.
   PubMed Web of Science ®Google Scholar
• Lacroix C, Laconi S, Angius F, et al. In vitro characterisation of a pleconaril/pirodavir-like compound with potent activity against rhinoviruses. Virol J. 2015 [cited 2015 July 14];12(1):106.
   PubMedGoogle Scholar
• Nikolaeva L, Galabov AS. Antiviral effect of the combination of enviroxime and disoxaril on coxsackievirus B1 infection. Acta Virol. 2000 Apr;44(2):73–78.
   PubMed Web of Science ®Google Scholar
• Chen T-C, Chang H-Y, Lin P-F, et al. Novel antiviral agent DTriP-22 targets RNA-dependent RNA polymerase of enterovirus 71. Antimicrob Agents Chemother. 2009;53(7):2740.
   PubMed Web of Science ®Google Scholar
• Goldhill DH, Te Velthuis AJW, Fletcher RA, et al. The mechanism of resistance to favipiravir in influenza. Proc Natl Acad Sci U S A. 2018;115(45):11613–11618.
   PubMed Web of Science ®Google Scholar
• Chen J, Ye X, Zhang X-Y, et al. Coxsackievirus A10 atomic structure facilitating the discovery of a broad-spectrum inhibitor against human enteroviruses. Cell Discov. 2019 [cited 2019 Jan 15];5(1):4.
   PubMedGoogle Scholar
• Woods MG, Diana GD, Rogge MC, et al. In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother. 1989 Dec;33(12):2069–2074.
   PubMed Web of Science ®Google Scholar
• Weng T-Y, Chen L-C, Shyu H-W, et al. Lactoferrin inhibits enterovirus 71 infection by binding to VP1 protein and host cells. Antiviral Res. 2005 [cited 2005 July 01];67(1):31–37.
   PubMed Web of Science ®Google Scholar
• Deng C-L, Yeo H, Ye H-Q, et al. Inhibition of enterovirus 71 by adenosine analog NITD008. J Virol. 2014;88(20):11915.
   PubMed Web of Science ®Google Scholar
• Smith TJ, Kremer MJ, Luo M, et al. The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating. Science (New York, NY). 1986 Sep 19;233(4770):1286–1293.
   Google Scholar
• Park KS, Choi YJ, Park JS. Enterovirus infection in Korean children and anti-enteroviral potential candidate agents. Korean J Pediatr. 2012;55(10):359–366.
   PubMedGoogle Scholar
• Tijsma A, Franco D, Tucker S, et al. The capsid binder vapendavir and the novel protease inhibitor SG85 inhibit enterovirus 71 replication. Antimicrob Agents Chemother. 2014;58(11):6990.
   PubMed Web of Science ®Google Scholar
• Zhang G, Zhou F, Gu B, et al. In vitro and in vivo evaluation of ribavirin and pleconaril antiviral activity against enterovirus 71 infection. Arch Virol. 2012 Apr;157(4):669–679.
   PubMed Web of Science ®Google Scholar
• Solomon T. 21 - Virus infections of the nervous system. In: Farrar J, Hotez PJ, Junghanss T, et al., editors. Manson’s tropical infectious diseases (Twenty-third Edition). London: W.B. Saunders; 2014. p. 242–72.e5.
   Google Scholar
• Smee DF, Evans WJ, Nicolaou KC, et al. Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds. Antiviral Res. 2016;131:61–65.
   PubMed Web of Science ®Google Scholar
• JaeHyoung S, Sang-Gu Y, Eun-Hye H, et al. Antiviral activity of hederasaponin B from hedera helix against enterovirus 71 subgenotypes C3 and C4a. Biomol Ther (Seoul). 2014 Jan;22(1):41–46.
   PubMed Web of Science ®Google Scholar
• Buontempo PJ, Cox S, Wright-Minogue J, et al. SCH 48973: a potent, broad-spectrum, antienterovirus compound. Antimicrob Agents Chemother. 1997;41(6):1220–1225.
   PubMed Web of Science ®Google Scholar
• Tan J, George S, Kusov Y, et al. 3C protease of enterovirus 68: structure-based design of Michael acceptor inhibitors and their broad-spectrum antiviral effects against picornaviruses. J Virol. 2013 Apr;87(8):4339–4351.
   PubMed Web of Science ®Google Scholar
• Ren P, Zheng Y, Wang W, et al. Suramin interacts with the positively charged region surrounding the 5-fold axis of the EV-A71 capsid and inhibits multiple enterovirus A. Sci Rep. 2017;7:42902. 02/20/online
   PubMed Web of Science ®Google Scholar
• Tsai F-J, Lin C-W, Lai -C-C, et al. Kaempferol inhibits enterovirus 71 replication and internal ribosome entry site (IRES) activity through FUBP and HNRP proteins. Food Chem. 2011 [cited 2011 Sep 15];128(2):312–322.
   PubMed Web of Science ®Google Scholar
• Lin CW, Wu CF, Hsiao NW, et al. Aloe-emodin is an interferon-inducing agent with antiviral activity against Japanese encephalitis virus and enterovirus 71. Int J Antimicrob Agents. 2008 Oct;32(4):355–359.
   PubMed Web of Science ®Google Scholar
• Wang J, Wu Z, Jin Q. COPI is required for enterovirus 71 replication. Plos One. 2012;7(5):e38035.
   PubMed Web of Science ®Google Scholar
• Nebenführ A, Ritzenthaler C, Robinson DG, et al. Deciphering an enigmatic inhibitor of secretion. Plant Physiol. 2002;130(3):1102.
   PubMed Web of Science ®Google Scholar
• Venditto VJ, Simanek EE. Cancer therapies utilizing the camptothecins: a review of the in vivo literature. Mol Pharm. 2010;7(2):307–349.
   PubMed Web of Science ®Google Scholar
• Wyde PR, Six HR, Wilson SZ, et al. Activity against rhinoviruses, toxicity, and delivery in aerosol of enviroxime in liposomes. Antimicrob Agents Chemother. 1988;32(6):890.
   PubMed Web of Science ®Google Scholar
• Xiao X, Lei X, Zhang Z, et al. Enterovirus 3A facilitates viral replication by promoting phosphatidylinositol 4-kinase IIIβ-ACBD3 interaction. J Virol. 2017;91(19):e00791–17.
   PubMed Web of Science ®Google Scholar
• van der Linden L, van der Schaar HM, Lanke KHW, et al. Differential effects of the putative GBF1 inhibitors Golgicide A and AG1478 on enterovirus replication. J Virol. 2010;84(15):7535–7542.
   PubMed Web of Science ®Google Scholar
• Arita M, Philipov S, Galabov AS. Phosphatidylinositol 4-kinase III beta is the target of oxoglaucine and pachypodol (Ro 09-0179) for their anti-poliovirus activities, and is located at upstream of the target step of brefeldin A. Microbiol Immunol. 2015 [cited 2015 June 01];59(6):338–347.
   PubMed Web of Science ®Google Scholar
• Miles SL, McFarland M, Niles RM. Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human disease. Nutr Rev. 2014 [cited 2014 Nov 01];72(11):720–734.
   PubMed Web of Science ®Google Scholar
• Li X, Liu Y, Wu T, et al. The antiviral effect of baicalin on enterovirus 71 in vitro. Viruses. 2015;7(8):4756–4771.
   PubMed Web of Science ®Google Scholar
• Yang Y, Xiu J, Liu J, et al. Chebulagic acid, a hydrolyzable tannin, exhibited antiviral activity in vitro and in vivo against human enterovirus 71. Int J Mol Sci. 2013 May 3;14(5):9618–9627.
   PubMed Web of Science ®Google Scholar
• Zhu Q-C, Wang Y, Liu Y-P, et al. Inhibition of enterovirus 71 replication by chrysosplenetin and penduletin. Eur J Pharm Sci. 2011 [cited 2011 Oct 09];44(3):392–398.
   PubMed Web of Science ®Google Scholar
• Rivero-Buceta E, Sun L, Martínez-Gualda B, et al. Optimization of a class of tryptophan dendrimers that inhibit hiv replication leads to a selective, specific, and low-nanomolar inhibitor of clinical isolates of enterovirus A71. Antimicrob Agents Chemother. 2016;60(8):5064.
   PubMed Web of Science ®Google Scholar
• Ho HY, Cheng ML, Weng SF, et al. Antiviral effect of epigallocatechin gallate on enterovirus 71. J Agric Food Chem. 2009 Jul 22;57(14):6140–6147.
   PubMed Web of Science ®Google Scholar
• Yang Y, Zhang L, Fan X, et al. Antiviral effect of geraniin on human enterovirus 71 in vitro and in vivo. Bioorg Med Chem Lett. 2012 Mar 15;22(6):2209–2211.
   PubMed Web of Science ®Google Scholar
• Liu J, Yang Y, Xu Y, et al. Lycorine reduces mortality of human enterovirus 71-infected mice by inhibiting virus replication. Virol J. 2011 Oct 27;8:483.
   PubMed Web of Science ®Google Scholar
• Yang Y, Xiu J, Zhang X, et al. Antiviral effect of matrine against human enterovirus 71. Molecules. 2012 Aug 29;17(9):10370–10376.
   PubMed Web of Science ®Google Scholar
• Yang Y, Xiu J, Zhang L, et al. Antiviral activity of punicalagin toward human enterovirus 71 in vitro and in vivo. Phytomedicine. 2012 Dec 15;20(1):67–70.
   PubMed Web of Science ®Google Scholar
• Choi HJ, Song JH, Lim CH, et al. Anti-human rhinovirus activity of raoulic acid from Raoulia australis. J Med Food. 2010 Apr;13(2):326–328.
   PubMed Web of Science ®Google Scholar
• Balouiri M, Sadiki M, Ibnsouda SK. Methods for in vitro evaluating antimicrobial activity: a review. J Pharm Anal. 2016 [cited 2016 April 01];6(2):71–79.
   PubMed Web of Science ®Google Scholar
• Zheng W, Thorne N, McKew JC. Phenotypic screens as a renewed approach for drug discovery. Drug Discov Today. 2013 [cited 2013 Nov 01];18(21):1067–1073.
   PubMed Web of Science ®Google Scholar
• Yin Y, Xu Y, Ou Z, et al. An antiviral drug screening system for enterovirus 71 based on an improved plaque assay: a potential high-throughput method. J Med Virol. 2019 cited 2019 March 22;91(8):1440–1447.
   Web of Science ®Google Scholar
• Hou H-Y, Lu -W-W, Wu K-Y, et al. Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site. J Gen Virol. 2016;97(5):1122–1133.
   PubMedGoogle Scholar
• Carella AM, Berman E, Maraone MP, et al. Idarubicin in the treatment of acute leukemias. An overview of preclinical and clinical studies. Haematologica. 1990 Mar-Apr;75(2):159–169.
   PubMed Web of Science ®Google Scholar
• Yang Y, Cao L, Gao H, et al. Discovery, optimization, and target identification of novel potent broad-spectrum antiviral inhibitors. J Med Chem. 2019 [cited 2019 April 25];62(8):4056–4073.
   PubMed Web of Science ®Google Scholar
• Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005 [cited 2005 March 01];4(3):206–220.
   PubMed Web of Science ®Google Scholar
• Li G, Gao Q, Yuan S, et al. Characterization of three small molecule inhibitors of enterovirus 71 identified from screening of a library of natural products. Antiviral Res. 2017 [cited 2017 July 01];143:85–96.
   PubMed Web of Science ®Google Scholar
• Wu KX, Chu JJ-H. Antiviral screen identifies EV71 inhibitors and reveals camptothecin-target, DNA topoisomerase 1 as a novel EV71 host factor. Antiviral Res. 2017 [cited 2017 July 01];143:122–133.
   PubMed Web of Science ®Google Scholar
• Wang Y, Li G, Yuan S, et al. In vitro assessment of combinations of enterovirus inhibitors against enterovirus 71. Antimicrob Agents Chemother. 2016;60(9):5357.
   PubMed Web of Science ®Google Scholar
• Xiao W, Lei F, Hengqiang Z, et al. CHAPTER 9 isolation and purification of natural products. In: Rostagno MA, Prado JM, editors. Natural product extraction: principles and applications: The Royal Society of Chemistry. 2013. p. 314–362.
   Google Scholar
• Trombetta RP, Dunman PM, Schwarz EM, et al. A high-throughput screening approach to repurpose FDA-approved drugs for bactericidal applications against staphylococcus aureus small-colony variants. mSphere. 2018;3(5):e00422–18.
   PubMed Web of Science ®Google Scholar
• Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2018;18:41. 10/12/online
   PubMed Web of Science ®Google Scholar
• Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004 [cited 2004 Aug 01];3(8):673–683.
   PubMed Web of Science ®Google Scholar
• Cagan R. Drug screening using model systems: some basics. Dis Model Mech. 2016;9(11):1241–1244.
   PubMed Web of Science ®Google Scholar
• Ren P, Zou G, Bailly B, et al. The approved pediatric drug suramin identified as a clinical candidate for the treatment of EV71 infection-suramin inhibits EV71 infection in vitro and in vivo. Emerg Microbes Infect. 2014;3(9):e62–e62.
   PubMedGoogle Scholar
• Kim C, Kang H, Kim DE, et al. Antiviral activity of micafungin against enterovirus 71. Virol J. 2016 [cited 2016 June 13];13(1):99.
   PubMedGoogle Scholar
• Gao Q, Yuan S, Zhang C, et al. Discovery of itraconazole with broad-spectrum in vitro antienterovirus activity that targets nonstructural protein 3A. Antimicrob Agents Chemother. 2015;59(5):2654.
   PubMed Web of Science ®Google Scholar
• Strating JRPM, van der Linden L, Albulescu L, et al. Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein. Cell Rep. 2015;10(4):600–615.
   PubMed Web of Science ®Google Scholar
• Lei X, Xiao X, Zhang Z, et al. The Golgi protein ACBD3 facilitates Enterovirus 71 replication by interacting with 3A. Sci Rep. 2017;7:44592.
   PubMed Web of Science ®Google Scholar
• Ulferts R, de Boer SM, van der Linden L, et al. Screening of a library of FDA-approved drugs identifies several enterovirus replication inhibitors that target viral protein 2C. Antimicrob Agents Chemother. 2016;60(5):2627.
   PubMed Web of Science ®Google Scholar
• Kieffer TL, George S. Resistance to hepatitis C virus protease inhibitors. Curr Opin Virol. 2014 Oct;8:16–21.
   PubMed Web of Science ®Google Scholar
• Oberste MS, Maher K, Pallansch MA. Evidence for frequent recombination within species human enterovirus B based on complete genomic sequences of all thirty-seven serotypes. J Virol. 2004 Jan;78(2):855–867.
   PubMed Web of Science ®Google Scholar
• Yip CC, Lau SK, Lo JY, et al. Genetic characterization of EV71 isolates from 2004 to 2010 reveals predominance and persistent circulation of the newly proposed genotype D and recent emergence of a distinct lineage of subgenotype C2 in Hong Kong. Virol J. 2013 Jul 4;10:222.
   PubMed Web of Science ®Google Scholar
• Sanjuan R, Nebot MR, Chirico N, et al. Viral mutation rates. J Virol. 2010 Oct;84(19):9733–9748.
   PubMed Web of Science ®Google Scholar
• Pirrone V, Thakkar N, Jacobson JM, et al. Combinatorial approaches to the prevention and treatment of HIV-1 infection. Antimicrob Agents Chemother. 2011 May;55(5):1831–1842.
   PubMed Web of Science ®Google Scholar
• Furman PA, Fyfe JA, St Clair MH, et al. Phosphorylation of 3ʹ-azido-3ʹ-deoxythymidine and selective interaction of the 5ʹ-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8333–8337.
   PubMed Web of Science ®Google Scholar
• Eron JJ Jr. HIV-1 protease inhibitors. Clin Infect Dis. 2000 Jun;30(Suppl 2):S160–70.
   PubMed Web of Science ®Google Scholar
• Lobritz MA, Ratcliff AN, Arts EJ. HIV-1 entry, inhibitors, and resistance. Viruses. 2010 May;2(5):1069–1105.
   PubMed Web of Science ®Google Scholar
• Bauer L, Lyoo H, van der Schaar HM, et al. Direct-acting antivirals and host-targeting strategies to combat enterovirus infections. Curr Opin Virol. 2017 Jun;24:1–8.
   PubMed Web of Science ®Google Scholar
• Lin K, Gallay P. Curing a viral infection by targeting the host: the example of cyclophilin inhibitors. Antiviral Res. 2013 Jul;99(1):68–77.
   PubMed Web of Science ®Google Scholar
• van der Schaar HM, Leyssen P, Thibaut HJ, et al. A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase IIIbeta. Antimicrob Agents Chemother. 2013 Oct;57(10):4971–4981.
   PubMed Web of Science ®Google Scholar
• Zeisel MB, Lupberger J, Fofana I, et al. Host-targeting agents for prevention and treatment of chronic hepatitis C – perspectives and challenges. J Hepatol. 2013 Feb;58(2):375–384.
   PubMed Web of Science ®Google Scholar
• Lee SM, Yen HL. Targeting the host or the virus: current and novel concepts for antiviral approaches against influenza virus infection. Antiviral Res. 2012 Dec;96(3):391–404.
   PubMed Web of Science ®Google Scholar
• Szweykowska-Kulinska Z, Jarmolowski A, Figlerowicz M. RNA interference and its role in the regulation of eucaryotic gene expression. Acta Biochim Pol. 2003;50(1):217–229.
   PubMed Web of Science ®Google Scholar
• Zhou R, Rana TM. RNA-based mechanisms regulating host-virus interactions. Immunol Rev. 2013 May;253(1):97–111.
   PubMed Web of Science ®Google Scholar
• Wu KX, Phuektes P, Kumar P, et al. Human genome-wide RNAi screen reveals host factors required for enterovirus 71 replication. Nat Commun. 2016 Oct 17;7:13150.
   PubMed Web of Science ®Google Scholar
• Coyne CB, Bozym R, Morosky SA, et al. Comparative RNAi screening reveals host factors involved in enterovirus infection of polarized endothelial monolayers. Cell Host Microbe. 2011 Jan 20;9(1):70–82.
   PubMed Web of Science ®Google Scholar
• Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov. 2002 Sep;1(9):727–730.
   PubMed Web of Science ®Google Scholar
• Jean Beltran PM, Cook KC, Cristea IM. Exploring and exploiting proteome organization during viral infection. J Virol. 2017 Sep 15;91:18.
   Web of Science ®Google Scholar
• Chan SY, Sam IC, Lai JK, et al. Cellular proteome alterations in response to enterovirus 71 and coxsackievirus A16 infections in neuronal and intestinal cell lines. J Proteomics. 2015 Jul 1;125:121–130.
   PubMed Web of Science ®Google Scholar
• Lee JJ, Seah JB, Chow VT, et al. Comparative proteome analyses of host protein expression in response to enterovirus 71 and coxsackievirus A16 infections. J Proteomics. 2011 Sep 6;74(10):2018–2024.
   PubMed Web of Science ®Google Scholar
• Clemen CS, Marko M, Strucksberg KH, et al. VCP and PSMF1: antagonistic regulators of proteasome activity. Biochem Biophys Res Commun. 2015 Aug 7;463(4):1210–1217.
   PubMed Web of Science ®Google Scholar
• Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture. Oncogene. 2004 Mar 15;23(11):1972–1984.
   PubMed Web of Science ®Google Scholar
• Kuo RL, Lin YH, Wang RY, et al. Proteomics analysis of EV71-infected cells reveals the involvement of host protein NEDD4L in EV71 replication. J Proteome Res. 2015 Apr 3;14(4):1818–1830.
   PubMed Web of Science ®Google Scholar
• Wang RY, Kuo RL, Ma WC, et al. Heat shock protein-90-beta facilitates enterovirus 71 viral particles assembly. Virology. 2013 Sep 1;443(2):236–247.
   PubMed Web of Science ®Google Scholar
• Tsou YL, Lin YW, Chang HW, et al. Heat shock protein 90: role in enterovirus 71 entry and assembly and potential target for therapy. PLoS One. 2013;8(10):e77133.
   PubMed Web of Science ®Google Scholar
• Too IHK, Bonne I, Tan EL, et al. Prohibitin plays a critical role in Enterovirus 71 neur1opathogenesis. PLoS Pathog. 2018 Jan;14(1):e1006778.
   PubMed Web of Science ®Google Scholar
• Peng YT, Chen P, Ouyang RY, et al. Multifaceted role of prohibitin in cell survival and apoptosis. Apoptosis. 2015 Sep;20(9):1135–1149.
   PubMed Web of Science ®Google Scholar
• Rajalingam K, Rudel T. Ras-Raf signaling needs prohibitin. Cell Cycle. 2005 Nov;4(11):1503–1505.
   PubMed Web of Science ®Google Scholar
• Polier G, Neumann J, Thuaud F, et al. The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem Biol. 2012 Sep 21;19(9):1093–1104.
   PubMedGoogle Scholar
• Li-Weber M. Molecular mechanisms and anti-cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines). Int J Cancer. 2015 Oct 15;137(8):1791–1799.
   PubMed Web of Science ®Google Scholar
• KP C, Minhajuddin M, Corbett C, et al. Flavaglines target primitive leukemia cells and enhance anti-leukemia drug activity. Leukemia. 2014 Oct;28(10):1960–1968.
   PubMed Web of Science ®Google Scholar
• Yang Y, Franc V, Heck AJR. Glycoproteomics: a balance between high-throughput and in-depth analysis. Trends Biotechnol. 2017 Jul;35(7):598–609.
   PubMed Web of Science ®Google Scholar
• Bagdonaite I, Norden R, Joshi HJ, et al. A strategy for O-glycoproteomics of enveloped viruses–the O-glycoproteome of herpes simplex virus type 1. PLoS Pathog. 2015 Apr;11(4):e1004784.
   PubMed Web of Science ®Google Scholar
• Yang W, Zhou JY, Chen L, et al. Glycoproteomic analysis identifies human glycoproteins secreted from HIV latently infected T cells and reveals their presence in HIV+ plasma. Clin Proteomics. 2014 Mar 6;11(1):9.
   PubMedGoogle Scholar
• Su PY, Wang YF, Huang SW, et al. Cell surface nucleolin facilitates enterovirus 71 binding and infection. J Virol. 2015 Apr;89(8):4527–4538.
   PubMed Web of Science ®Google Scholar
• Lu T, Jackson MW, Singhi AD, et al. Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFkappaB. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16339–16344.
   PubMed Web of Science ®Google Scholar
• Wang B, Zhang X, Zhao Z. Validation-based insertional mutagenesis for identification of Nup214 as a host factor for EV71 replication in RD cells. Biochem Biophys Res Commun. 2013 Aug 2;437(3):452–456.
   PubMed Web of Science ®Google Scholar
• Staring J, van Den Hengel LG, Raaben M, et al. KREMEN1 is a host entry receptor for a major group of enteroviruses. Cell Host Microbe. 2018 May 9;23(5):636–43 e5.
   PubMed Web of Science ®Google Scholar
• Mishra SK, Funair L, Cressley A, et al. High-affinity Dkk1 receptor Kremen1 is internalized by clathrin-mediated endocytosis. PLoS One. 2012;7(12):e52190.
   PubMed Web of Science ®Google Scholar
• Zebisch M, Jackson VA, Zhao Y, et al. Structure of the dual-mode wnt regulator kremen1 and insight into ternary complex formation with LRP6 and dickkopf. Structure. 2016 Sep 6;24(9):1599–1605.
   PubMed Web of Science ®Google Scholar
• Gilbert IH. Drug discovery for neglected diseases: molecular target-based and phenotypic approaches. J Med Chem. 2013 Oct 24;56(20):7719–7726.
   PubMed Web of Science ®Google Scholar
• Morimoto BH, Castelloe E, Fox AW. Safety pharmacology in drug discovery and development. Handb Exp Pharmacol. 2015;229:65–80.
   PubMedGoogle Scholar
• Gebre M, Nomburg JL, Gewurz BE. CRISPR-Cas9 genetic analysis of virus-host interactions. Viruses. 2018 Jan 30;10:2.
   Web of Science ®Google Scholar
• Han J, Perez JT, Chen C, et al. Genome-wide CRISPR/Cas9 screen identifies host factors essential for influenza virus replication. Cell Rep. 2018 Apr 10;23(2):596–607.
   PubMed Web of Science ®Google Scholar
• Hwang B, Lee JH, Bang D. Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp Mol Med. 2018 Aug 7;50(8):96.
   PubMedGoogle Scholar
• Zhou H, Guo S, Sun Y, et al. Screening the action targets of enterovirus 71 in human SH-SY5Y cells using RNA sequencing data. Viral Immunol. 2019 May 7.
   PubMed Web of Science ®Google Scholar
• Shih C, Liao CC, Chang YS, et al. Immunocompetent and immunodeficient mouse models for enterovirus 71 pathogenesis and therapy. Viruses. 2018;10:12.
   Web of Science ®Google Scholar
• Yang CH, Liang CT, Jiang ST, et al. A novel murine model expressing a chimeric mSCARB2/hSCARB2 receptor is highly susceptible to oral infection with clinical isolates of enterovirus 71. J Virol. 2019;93(11):pii: e00183-19.
   Web of Science ®Google Scholar
• Wang ZL, Xia AM, Li YF, et al. Socioeconomic burden of hand, foot and mouth disease in children in Shanghai, China. Epidemiol Infect. 2016 Jan;144(1):138–143.
   PubMed Web of Science ®Google Scholar
• Cheong K. Child caught HFMD? It could cost family $1,200. 2014; [cited 2019 Aug 27]. Available from: https://www.straitstimes.com/singapore/health/child-caught-hfmd-it-could-cost-family-1200
   Google Scholar
• Singapore MoH. Weekly infectious disease bulletin. 2019. Available from: https://www.moh.gov.sg/resources-statistics/infectious-disease-statistics/2018/weekly-infectious-diseases-bulletin
   Google Scholar
• Teng S, Zhao SY, Wei Y, et al. [Observation on virus shedding periods of enterovirus-71 and coxsackievirus A 16 monitored by nucleic acids determination in stool samples of children with hand, foot and mouth disease]. Zhonghua Er Ke Za Zhi. 2013 Oct;51(10):787–792.
   PubMedGoogle Scholar