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. An isolated polypeptide consisting of an enzymatically inactive 2′,5′ oligoadenylate synthetase (OAS) with antiviral activity having the sequence of SEQ ID NO:1 except that the OAS polypeptide has (a) a mutation at position 75 and/or 77 of SEQ ID NO:1, 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 isolated polypeptide of claim 1 , wherein the mutation replaces Asp with Ala at positions 75 and/or 77.
3. The isolated polypeptide of claim 1 , wherein the amino acid mutation is the substitution of Gly with Ser at position 162.
4. The isolated polypeptide of claim 1 , wherein the isolated polypeptide is modified with polyethylene glycol.
5. The isolated polypeptide of claim 4 , wherein the isolated polypeptide is covalently bonded to polyethylene glycol at one or more cysteine residues.
6. A pharmaceutical composition comprising an isolated polypeptide of claim 1 .
7. The isolated polypeptide of claim 3 , wherein the amino acid mutation is the deletion of Met at position 1.
8. The isolated polypeptide 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 isolated polypeptide of claim 3 , wherein the amino acid mutation is the substitution of Asn with Asp at position 31.
10. The isolated polypeptide of claim 3 , wherein the amino acid mutation is the substitution of Phe with Leu at position 115.
11. The isolated polypeptide of claim 3 , wherein the amino acid mutation is the substitution of Gly with Arg at position 127.
12. The isolated polypeptide of claim 3 , wherein the amino acid mutation is the substitution of Asn with Thr at position 280.
13. The isolated polypeptide of claim 3 , wherein the amino acid mutation is the substitution of Pro with Ser at position 330.
14. The isolated polypeptide of claim 3 , wherein the amino acid mutation is the deletion of Leu at position 346.