Preventing and treating sepsis
Provided are polypeptides comprising a variant activated protein C comprising one or more amino acid substitutions selected from the group consisting of K146R, D172N, C212R, K146G, R147G, R177G and combinations thereof. Also provided are nucleic acids encoding the polypeptides, and cells, compositions and kits containing the polypeptides and nucleic acids. Also provided are methods of treating sepsis in a subject comprising administering to the subject one or more of the provided polypeptides or nucleic acids. Methods of screening for polypeptides with enhanced activated protein C and for an agent for treatment of sepsis are provided. Finally, provided is a method of treating sepsis in a subject comprising administering to the subject a pharmaceutical composition comprising one or more RGD-containing peptides.
1. An isolated polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 1 and one or more amino acid substitutions selected from the group consisting of K146R, C212R, K146G, R147G, and R177G; wherein said isolated polypeptide is an activated protein C with serine protease activity.
2. The isolated polypeptide of claim 1 , wherein said isolated polypeptide comprises the amino acid substitution(s) selected from the group consisting of K146G and R147G; R177G, K146G, and R147G; C212R, K146G, and R147G; C212R and R177G; and K146R.
3. The isolated polypeptide of claim 1 , wherein said isolated polypeptide further comprises the amino acid substitutions selected from the group consisting of RR229/230AA; KKK191-193AAA; and KKK191-193AAA and RR229/230AA.
4. A composition comprising the isolated polypeptide of claim 1 and a pharmaceutically acceptable excipient.
5. A method of treating sepsis in a subject comprising administering the isolated polypeptide of claim 1 to a subject having sepsis.