Abstract
Pyridyl imidazolidinone is a novel class of capsid binder which can inhibit enterovirus 71 (EV71). In this study, we tested the susceptibility of six recombinant viruses with different single-site mutations in VP1. Eleven modified pyridyl imidazolidinones were synthesized and used to probe the interaction between these compounds and the EV71 VP1 protein. We found that the D31N or E98K mutant viruses were susceptible to bulkier compounds, which suggested that mutations at these two sites in VP1 may widen the hydrophobic pocket of VP1, allowing bulkier compounds to enter and interfere VP1-receptor binding. Additionally, the Y116H mutant was more resistant to pyridyl imidazolidinone compounds containing a methyl group in the central position of the hydrophobic linker. When a trifluoromethyl group was substituted for the methyl group in the middle of the linker chain, the inhibitory effect was totally abolished in the Y116H mutant, suggesting that the interaction between Tyr (Y) 116 of VP1 and the central position of the linker chain of pyridyl imidazolodinone is very important for drug efficacy. A V192M mutant was resistant to most of the derivatives, indicating that residue 192 is a key mutation for resistance to pyridyl imidazolidinone.
Similar content being viewed by others
References
AbuBakar S, Chan YF, Lam SK (2002) Outbreaks of enterovirus 71 infection. N Engl J Med 342:355–356
Alexander JPJ, Baden L, Pallansch MA, Anderson LJ (1994) Enterovirus 71 infections and neurologic disease—United States, 1977–1991. J Infect Dis 169:905–908
Bergelson JM, Shepley MP, Chan BM, Hemler ME, Finberg RW (1992) Identification of the integrin VLA-2 as a receptor for echovirus 1. Science 255:1718–1720
Billich A (2000) Pleconaril Sanofi Synthelabo/ViroPharma. Curr Opin Investig Drugs 1:303–307
Chang LY, Huang YC, Lin TY (1998) Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease. Lancet 352:367–368
Chang CS, Lin YT, Shih SR, Lee CC, Lee YC, Tai CL, Tseng SN, Chern JH (2005) Design, synthesis, and antipicornavirus activity of 1-[5-(4-Arylphenoxy)alkyl]-3-pyridin-4-ylimidazolidin-2-one derivatives. J Med Chem 48:3522–3535
Chern JH, Lee CC, Chang CS, Lee YC, Tai CL, Lin YT, Shia KS, Lee CY, Shih SR (2004) Synthesis and antienteroviral activity of a series of novel, oxime ether-containing pyridyl imidazolidinones. Bioorg Med Chem Lett 14:5051–5056
Chern JH, Shia KS, Hsu TA, Tai CL, Lee CC, Lee YC, Chang CS, Tseng SN, Shih SR (2004) Design, synthesis, and structure-activity relationships of pyrazolo[3,4-d]pyrimidines: a novel class of potent enterovirus inhibitors. Bioorg Med Chem Lett 14:2519–2525
Chern JH, Chang CS, Tai CL, Lee YC, Lee CC, Kang IJ, Lee CY, Shih SR (2005) Synthesis and antipicornavirus activity of (R)- and (S)-1-[5-(4′-chlorobiphenyl-4-yloxy)-3-methylpentyl]-3-pyridin-4-yl-imidazolidin-2-one. Bioorg Med Chem Lett 15:4206–4211
Diana GD, McKinlay MA, Otto MJ, Akullian V, Oglesby C (1985) [[(4,5-Dihydro-2-oxazolyl)phenoxy]alkyl]isoxazoles. Inhibitors of picornavirus uncoating. J Med Chem 28:1906–1910
Dove AW, Racaniello VR (2000) An antiviral compound that blocks structural transitions of poliovirus prevents receptor binding at low temperatures. J Virol 74:3929–3931
Gilbert GL, Dickson KE, Waters MJ, Kennett ML, Land SA, Sneddon M (1988) Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement. Pediatr Infect Dis J 7:484–488
Greve JM, Davis G, Meyer AM, Forte CP, Yost SC, Marlor CW, Kamarck ME, McClelland A (1989) The major human rhinovirus receptor is ICAM-1. Cell 56:839–847
Ho M (2000) Enterovirus 71: the virus, its infections and outbreaks. J Microbiol Immunol Infect 33:205–216
Ho M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, Wang JR, Shih SR (1999) An epidemic of enterovirus 71 infection in Taiwan. N Engl J Med 341:929–935
Hogle JM, Chow M, Filman DJ (1985) Three-dimensional structure of poliovirus at 2.9 A resolution. Science 229:1358–1365
McKinlay MA (1985) WIN 51711, a new systematically active broad-spectrum antipicornavirus agent. J Antimicrob Chemother 16:284–286
Mendelsohn CL, Wimmer E, Racaniello VR (1989) Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 56:855–865
Modlin JF, Dagan R, Berlin LE, Virshup DM, Yolken RH, Menegus M (1991) Focal encephalitis with enterovirus infections. Pediatrics 88:841–845
Moore DM, Cowan KM (1978) Effect of trypsin and chymotrypsin on the polypeptides of large and small plaque variants of foot-and-mouth disease virus: relationship to specific antigenicity and infectivity. J Gen Virol 41:549–562
Muckelbauer JK, Kremer M, Minor I, Diana G, Dutko FJ, Groarke J, Pevear DC, Rossmann MG (1995) The structure of coxsackievirus B3 at 3.5 A resolution. Structure 3:653–667
Otto MJ, Fox MP, Fancher MJ, Kuhrt MF, Diana GD, McKinlay MA (1985) In vitro activity of WIN 51711, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother 27:883–886
Pevear DC, Fancher MJ, Felock PJ, Rossmann MG, Miller MS, Diana G, Treasurywala AM, McKinlay MA, Dutko FJ (1989) Conformational change in the floor of the human rhinovirus canyon blocks adsorption to HeLa cell receptors. J Virol 63:2002–2007
Pevear DC, Tull TM, Seipel ME, Groarke JM (1999) Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother 43:2109–2115
Rogers JM, Diana GD, McKinlay MA (1999) Pleconaril. A broad spectrum antipicornaviral agent. Adv Exp Med Biol 458:69–76
Romero JR (2001) Pleconaril: a novel antipicornaviral drug. Expert Opin Investig Drugs 10:369–379
Rossmann MG (1989) The canyon hypothesis. Hiding the host cell receptor attachment site on a viral surface from immune surveillance. J Biol Chem 264:14587–14590
Rossmann MG (1989) The canyon hypothesis. Viral Immunol 2:143–161
Rossmann MG, Johnson JE (1989) Icosahedral RNA virus structure. Annu Rev Biochem 58:533–573
Rossmann MG, Arnold E, Erickson JW, Frankenberger EA, Griffith JP, Hecht HJ, Johnson JE, Kamer G, Luo M, Mosser AG et al (1985) Structure of a human common cold virus and functional relationship to other picornaviruses. Nature 317:145–153
Rotbart HA (1999) Antiviral therapy for enteroviral infections. Pediatr Infect Dis J 18:632–633
Sawyer MH (1999) Enterovirus infections: diagnosis and treatment. Pediatr Infect Dis J 18:1033–1039
Shia KS, Li WT, Chang CM, Hsu MC, Chern JH, Leong MK, Tseng SN, Lee CC, Lee YC, Chen SJ, Peng KC, Tseng HY, Chang YL, Tai CL, Shih SR (2002) Design, synthesis, and structure-activity relationship of pyridyl imidazolidinones: a novel class of potent and selective human enterovirus 71 inhibitors. J Med Chem 45:1644–1655
Shih SR, Chen SJ, Hakimelahi GH, Liu HJ, Tseng CT, Shia KS (2004) Selective human enterovirus and rhinovirus inhibitors: an overview of capsid-binding and protease-inhibiting molecules. Med Res Rev 24:449–474
Shih SR, Tsai MC, Tseng SN, Won KF, Shia KS, Li WT, Chern JH, Chen GW, Lee CC, Lee YC, Peng KC, Chao YS (2004) Mutation in enterovirus 71 capsid protein VP1 confers resistance to the inhibitory effects of pyridyl imidazolidinone. Antimicrob Agents Chemother 48:3523–3529
van Wezel AL, van der Marel P, Hazendonk TG, Boer-Bak V, Henneke MA (1983) Antigenicity and immunogenicity of poliovirus capsid proteins. Dev Biol Stand 55:209–215
Woods MG, Diana GD, Rogge MC, Otto MJ, Dutko FJ, McKinlay MA (1989) In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother 33:2069–2074
Acknowledgments
We thank the NHRI and NSC for financially supporting this research under contract no. NSC-94IDP002-1.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Chen, TC., Liu, SC., Huang, PN. et al. Antiviral activity of pyridyl imidazolidinones against enterovirus 71 variants. J Biomed Sci 15, 291–300 (2008). https://doi.org/10.1007/s11373-007-9228-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11373-007-9228-5