Oligoadenylate synthetase (OAS)
The invention describes novel pharmaceutical compositions for the treatment of virus infections and cancer. The pharmaceutical compositions include mutant oligoadenylate synthetases (OAS) that have either enhanced cell permeability, reduced oxidative potential, improved antiviral activity, improved enzymatic activity, or absent enzymatic activity. The pharmaceutical compositions have improved drug properties and retain or have enhanced antiviral activity relative to their native forms. The pharmaceutical compositions further include chemically modified oligoadenylate synthetases, such chemical modifications being designed to increase serum stability and reduce immunogenicity in vivo. Such chemical modifications further increase drug stability and manufacturability in vitro. Compositions composed of more than ninety novel modifications are described. Also described are antibodies to polypeptides of the invention.
1. A method of treating a viral infection in a mammal in need thereof, comprising administering to said mammal a pharmaceutical composition comprising an antiviral but enzymatically inactive 2′,5′ oligoadenylate synthetase (OAS) polypeptide consisting of SEQ ID NO. 1 except that the OAS polypeptide has (a) a mutation at position 75 and/or 77, and (b) an amino acid mutation at one or more of positions 1, 25, 31, 38, 45, 54, 109, 115, 127, 162, 177, 189, 219, 269, 280, 330, 331, and 346.
2. The method of claim 1 , wherein the mutation replaces Asp with Ala at positions 75 and/or 77.
3. The method of claim 1 , wherein the amino acid mutation is the substitution of Gly with Ser at position 162.
4. The method of claim 1 , wherein said viral infection is caused by a member of the Flaviviridae family, the Hepadnaviridae family, the Picornaviridae family, the Retroviridae family, the Coronaviridae family, the Rhabdoviridae family, the Paramyxoviridae family, the Papillomaviridae family, or the Herpesviridae family.
5. The method of claim 1 , wherein said viral infection is caused by Hepatitis C Virus, Yellow Fever Virus, West Nile Virus, Japanese Encephalitis Virus, Dengue Virus, Bovine Viral Diarrhea Virus, Hepatitis B Virus, Encephalomyocarditis Virus, Human Rhinovirus, Hepatitis A Virus, Human Immunodeficiency Virus, Simian Immunodeficiency Virus, Human T-Lymphotropic Virus, Rous Sarcoma Virus, SARS coronavirus, Rabies Virus, Vesicular Stomatitis Virus, Respiratory Syncytial Virus, Parainfluenza Virus, Human Papillomavirus, or Herpes Simplex Virus.
6. The method of claim 1 , wherein said treating is therapeutic or prophylactic.
7. The method of claim 3 , wherein the amino acid mutation is the deletion of Met at position 1.
8. The method of claim 3 , wherein the amino acid mutation is the substitution of Cys with Ala, Gly, Met, Ser, Thr, or no amino acid at position 25, 38, 45, 54, 109, 177, 189, 219, 269, or 331.
9. The method of claim 3 , wherein the amino acid mutation is the substitution of Asn with Asp at position 31.
10. The method of claim 3 , wherein the amino acid mutation is the substitution of Phe with Leu at position 115.
11. The method of claim 1 , wherein the amino acid mutation is the substitution of Gly with Arg at position 127.
12. The method of claim 3 , wherein the amino acid mutation is the substitution of Asn with Thr at position 280.
13. The method of claim 3 , wherein the amino acid mutation is the substitution of Pro with Ser at position 330.
14. The method of claim 3 , wherein the amino acid mutation is the deletion of Leu at position 346.