PDGF mutants and methods of use thereof
View Patent ↗Isolated polypeptides having enhanced affinity for a PDGF receptor and/or a VEGF receptor are provided. Compositions comprising the polypeptides and methods of use thereof are also provided.
1. An isolated polypeptide having an amino acid sequence comprising at least about 93% of SEQ ID NO: 1, wherein the polypeptide binds to a PDGF receptor and/or a VEGF receptor and increases PDGF and/or VEGF signaling in the cell, and wherein the polypeptide comprises at least one amino acid substitution resulting in a higher binding affinity to the receptor than a wild-type PDGF or VEGF polypeptide, wherein the at least one amino acid substitution is selected from the group consisting of: M12R, I13E, K17N, E21Y, V22L, E24R, R28N, R32I, N57Y, Q71M, and T101K, and any other amino acid substitutions are conservative amino acid substitutions or selected from the group consisting of 177F and K98R.
2. The isolated polypeptide of claim 1 wherein the polypeptide comprises at least one amino acid substitution at position 13, 17, 21, 22, 24, 28, 32, 57, 71, or 101.
3. The isolated polypeptide of claim 1 wherein the polypeptide has an amino acid sequence comprising at least 95% identity to any one of SEQ ID NOs: 2-9 and 11.
4. A composition for increasing PDGF and/or VEGF signaling in a subject, the composition comprising any polypeptide of claim 1 , and a pharmaceutically acceptable carrier.
5. An isolated nucleic acid that encodes for any polypeptide of claim 1 .
6. A vector comprising the isolated nucleic acid of claim 5 and a heterologous nucleic acid sequence.
7. A host cell expressing the vector of claim 6 .
8. The host cell of claim 7 wherein the host cell comprises a bacterial cell.
9. A method of increasing PDGF and/or VEGF signaling in a cell the method comprising administering the polypeptide of claim 1 to the cell.
10. A method of treating a disease or condition associated with abnormal PDGF and/or VEGF signaling in a subject in need thereof, the method comprising administering the polypeptide of claim 1 to the subject, wherein the disease or condition is associated with insufficient or reduced PDGF and/or VEGF signaling and administering the polypeptide increases PDGF and/or VEGF signaling in the subject.
11. The method of claim 10 wherein the method is for treating wounds and/or enhancing wound healing.
12. The method of claim 11 , further comprising administering becaplermin to the subject.
13. An isolated polypeptide having an amino acid sequence, wherein the polypeptide binds to a PDGF receptor and/or a VEGF receptor and increases PDGF and/or VEGF signaling in the cell, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 2-9 and 11.
14. The isolated polypeptide of claim 13 wherein the polypeptide has an amino acid sequence consisting of any one of SEQ ID NOs: 2-9 and 11.
15. A composition for increasing PDGF and/or VEGF signaling in a subject, the composition comprising any polypeptide of claim 13 , and a pharmaceutically acceptable carrier.
16. An isolated nucleic acid that encodes for any polypeptide of claim 13 .
17. A vector comprising the isolated nucleic acid of claim 16 and a heterologous nucleic acid sequence.
18. A host cell expressing the vector of claim 17 .
19. A method of increasing PDGF and/or VEGF signaling in a cell the method comprising administering the polypeptide of claim 18 to the cell.
20. A method of treating a disease or condition associated with abnormal PDGF and/or VEGF signaling in a subject in need thereof, the method comprising administering the polypeptide of claim 13 to the subject, wherein the disease or condition is associated with insufficient or reduced PDGF and/or VEGF signaling and administering the polypeptide increases PDGF and/or VEGF signaling in the subject.