Summary
In this report we describe the antiviral activity of 5,5′-diphenyl-3,3′-diisothiazole disulfide (DID) and discuss its mode of action. DID selectively inhibits the replication of poliovirus type 1 (therapeutic index=255) by affecting some early process of the virus growth cycle. The compound does not interfere with adsorption and internalization of virus to HEp-2 cells, nor with uncoating of the viral RNA. However, no viral RNA synthesis occurs after 2h post-infection in the presence of 50µM DID.
Thus, we investigated some molecular events in poliovirus replication occurring between uncoating and viral RNA synthesis. In our experimental design, we studied the activity of RNA polymerase complex isolated from HEp-2 infected cells in the presence or absence of DID. Our results showed that the RNA polymerase complex was formed in the presence of DID. On the contrary, DID markedly inhibited poliovirus RNA synthesis in a cell-free system using RNA polymerase complex isolated from infected cells.
These findings indicate that DID may exert its antiviral activity by preventing viral RNA chain elongation via the inhibition of replicase activity and/or interfering with viral RNA polymerase complex.
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Andries K, Dewindt B, Snoeks J, Willebrords R, Van Eemeren K, Stokbroekx R, Janssen PAJ (1992) In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity. Antimicrob Agents Chemother 36: 100–107
Caliguiri LA, Tamm I (1968) Action of guanidine on the replication of poliovirus RNA. Virology 35: 408–417
Caliguiri LA, Tamm I (1973) Guanidine and 2-(alpha-hydroxybenzyl)-benzimidazole (HBB): selective inhibitors of picornavirus multiplication. In: Carter W (ed) Selective inhibitors of viral functions. CRC Press, Boca Raton, pp 257–294
Castrillo JL, Vanden Berghe D, Carrasco L (1986) 3-methylquercetin is a potent and selective inhibitor of poliovirus RNA synthesis. Virology 152: 219–227
Condorelli P, Pappalardo G, Tornetta B (1967) Contributo alla conoscenza della reattività dei sali 3-imino-5-fenil-1,2 ditiolo. Ann Chim (Rome) 57: 471–485
Conti C, Tomao P, Genovese D, Desideri N, Stein ML, Orsi N (1992) Mechanism of action of the antirhinovirus flavonoid 4′,6-dicyanoflavan. Antimicrob Agents Chemother 36: 95–99
De Sena J, Mandel B (1976) Studies on the in vitro uncoating of poliovirus. I. Characterization of the modifying factor and the modifying reaction. Virology 70: 470–483
Diana GD, Otto MJ, McKinlay MA (1985) Inhibitors of picornavirus uncoating as antiviral agents. Pharmacol Ther 29: 287–297
Eggers HJ, Waidner E (1970) Effect of 2-(alpha-hydroxybenzyl)-benzimidazole and guanidine on the uncoating of echovirus 12. Nature 227: 952–953
Flanegan JB, Van Dike TA (1979) Isolation of a soluble and template-dependent poliovirus RNA polymerase that copies virion RNA in vitro. J Virol 32: 155–161
Fox MP, Otto MJ, McKinley MA (1986) The prevention of poliovirus and rhinovirus uncoating by WIN 51711: a new antiviral drug. Antimicrob Agents Chemother 30: 110–116
Garozzo A, Pinizzotto MR, Furneri PM, Baratta D, Guerrera F, Castro A, Tornetta B, Geremia E (1990) Inhibitory effect of 3-imino-5-phenyl-3H-1,2-dithiole on poliovirus type 1 replication in vitro. Antiviral Res 14: 267–277
Girard M (1969) In vitro synthesis of poliovirus ribonucleic acid: role of the replicative intermediate. J Virol 3: 376–384
Grandin A, Vialle J (1967) Synthesis and reactions of 5-aryl-3-imino-1,2-dithiole hydrochlorides. Bull Soc Chim Fr 5: 1851
Ishitsuka H, Ohsawa C, Ohiwa T, Umeda I, Suhara Y (1982) Antipicornavirus flavone Ro 09–0179. Antimicrob Agents Chemother 22: 611–616
Korant B, Butterworth B, Kauer J (1974) Zinc ions inhibit replication of rhinoviruses Nature 248: 588–590
Korant BD, Lonberg-Holm K, La Colla P (1984) Picornavirus and togaviruses: targets for the design of antivirals. In: De Clercq E, Walker RT (eds) Targets for the design of antiviral agents. Plenum, New York, pp 61–68
Mandel B (1967) The relationship between penetration and uncoating of poliovirus in HeLa cells. Virology 31: 702–712
McSharry JJ, Caliguiri A, Eggers HJ (1979) Inhibition of uncoating of poliovirus by arildone, a new antiviral drug. Virology 97: 307–315
Pinizzotto MR, Garozzo A, Furneri PM, Scalia G, Guerrera F, Tornetta B (1990) Studio in vitro dell'attivita' antivirale di alcuni 1,2-ditiolo-3oni: una nuova generazione di composti di sintesi. L'Igiene Moderna 94: 748–755
Pinizzotto MR, Garozzo A, Furneri PM, Castro A, Geremia E (1991) In vitro antiviral activity of four isothiazole derivatives against some DNA and RNA viruses. J Chemother 3 [Suppl] 4: 486–487
Pinizzotto MR, Garozzo A, Guerrera F, Castro A, La Rosa MG, Furneri PM, Geremia E (1992) In vitro antiviral activity of four isothiazole derivatives against poliovirus type 1. Antiviral Res 19: 29–41
Rightsel WA, Schneider HG, Sloan BJ, Graf PR, Miller FA, Bartz QR, Ehrlich J, Dixon GI (1964) Antiviral activity of gliotoxin and gliotoxin acetate. Nature 204: 1333–1334
Tershak DR (1982) Inhibition of poliovirus polymerase by guanidine in vitro. J Virol 41: 313–318
Tisdale M, Selway JWT (1983) Inhibition of an early stage of rhinovirus replication by dichloroflavan (BW683C). J Gen Virol 64: 795–803
Toney HL, Dulworth JK, Steward DL (1982) Antiviral activity and mechanism of 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrite (MDL-860). Antimicrob Agents Chemother 22: 635–638
Tornetta B (1960) Azione del P2S5 sul cianacetofenone sintesi ammino-ditiolica. Ann Chim (Rome) 50: 1811–1818
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Garozzo, A., Pinizzotto, M.R., Guerrera, F. et al. Antipoliovirus activity of isothiazole derivatives: mode of action of 5,5′-diphenyl-3,3′-diisothiazole disulfide (DID). Archives of Virology 135, 1–11 (1994). https://doi.org/10.1007/BF01309761
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DOI: https://doi.org/10.1007/BF01309761