Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1999-11-09
2001-04-03
Jones, Dameron (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S001650
Reexamination Certificate
active
06210653
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the use of low molecular weight sulfonated polystyrenes or copolymers of these compounds with carboxylic containing monomers as selective anti-viral agents against HIV and other enveloped viruses.
2. Prior Art
Bauman et al U.S. Pat. No. 2,835,655 May 1958
Persinski et al U.S. Pat. No. 3,952,805 August 1976
Peiffer et al U.S. Pat. No. 5,026,490 June 1991
OTHER PUBLICATIONS
Babe M. et al. Antimicrobial agents-Chemother 1988; 32: 1742-5. Sulfated polysaccharides are potent selective inhibitors of various enveloped viruses.
Mitsuya H. Looney, D. J. Kunos et al. Science 1988; 240: 646-9. Dextran sulfated suppressive of viruses in the HIV family. A. Helenius and K Simos. Biochimica et Biophysica Acta, 415(1975) 29-79.
SUMMARY OF THE INVENTION
Sulfated and sulfonated compounds containing hydrophobic backbones are well known to solubilize viral and bacterial membranes. Compounds such as fatty sulfated alcohols have powerful solubilizing properties which are used to dissolve viral membranes, but these materials had no cell protection from HIV induced death and the dextran sulfates had comperatively low activity. However, the model polystyrene sodium solfonates had high activity and the activity was highest at 4600 molecular weight see Table 1 and FIG.
1
.
We also tested sulfonated styrene maleic anhydride copolymers of very low molecular weight and these materials had also very high activity as they approached the 4600 molecular weight. It should be pointed out that the patent references of Bauman (column 3, lines 26-29), Persinski (column 4, lines 60-65), Peiffer (column 5, lines 32-35, 53-55), although disclosing a sulfonated styrene-maleic anhydride copolymer, failed to disclose their high anti-viral activity against the HIV virus at the low molecular weight range indicated above. These patents deal mainly with the synthesis of these compounds, Bauman U.S. Pat. No. 2,835,655 or their use in other applications Persinski U.S. Pat. No. 3,952,805 (Well cementing Method) and Peiffer U.S. Pat. No. 5,026,490 (Deflocculants in water based drilling fluids). We also studied the effect of polystyrene-maleic anhydride copolymers with molecular weight less than 10,000 and these materials not only had cell protection against HIV as indicated above, but they also had anti-viral activity against HIV-1 strain at subtoxic concentrations in plaque reduction assays with IC95's around 10 ug/ml. So these polymers not only protected the cells against HIV infection, but also attacked the virus itself.
The sulfonated polymers studied were made by well known methods involving sulfonation of polystyrene and polystyrene copolymers with sulfur trioxide in an appropiate solvent. The more active lower molecular weight fractions were obtained by separation using gel permeation techniques or were made directly from low molecular weight unsulfonated polymers.
We believe the anti-viral activity of these polymers is either due to the ability of these compounds to prevent attachment to the T cells and/or it is due to the ability of these polymers to complex with the virus and dissolve away the viral membrane exposing the harmless nuclocapsid. It should be mentioned that mamalian cells are not as susceptible to this type of disruption as are the viral and bacterial cells, and failure of the dextran sulfates and the sulfated fatty alcohols are due to the fact that the former does not have very hydrophobic backbones and the lattter have too low a molecular weight to be effective. In addition these styrene based polymers have very low toxicity to T-cells which makes them even more valuable as anti-viral agents. Table 1 shows that sulfonated polystyrene homopolymers have anti-viral activity against HIV although not as high as those of the sulfonated styrene maleic anhydride copolymers, similarly homopolymers of pure maleic anhydride have lower activity than the sulfonated styrene maleic anhydride copolymers with IC90 of 3.0.
REFERENCES:
patent: 2835655 (1958-05-01), Bauman
patent: 3952805 (1976-04-01), Persinski
patent: 5026490 (1991-06-01), Peiffer
patent: 5342646 (1994-08-01), Kleese et al.
Baba et al, Antimicrobial Agents and Chemotherapy, vol. 32, No. 11, pp. 1742-1745, ‘Sulfated Polysaccharide Are Potent and Selective Inhibitors of Various Enveloped Viruses, Including Herpes Simplex Virus, Cytomegalovirus, Vesicular Stomatitis Virus, and Human Immunodeficiency Virus’, Nov. 1988.*
Mitsuya et al, Science, vol. 240, pp. 646-649, Dextran Sulfate Suppression of Viruses in the HIV Family: Inhibition of Virion Binding to CD4+Cells, Apr. 1988.*
Helenius et al, Biochimica et al Biophysica Acta, vol. 415, pp. 29-79, ‘Solubilization of Membranes by Detergents’, 1975.
Bellettini Arturo G.
Bellettini Richard J.
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