Enzymatic removal of a protein amino-terminal sequence
AssigneeEli Lilly and Company
InventorsGerald W. Becker, Thomas C. Furman, Warren C. MacKellar, James P. McDonough
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Abstract
This disclosure relates to new compounds and to a process for the controlled conversion of such compounds to produce a Protein that comprises an amino acid sequence which is useful as a precursor to human insulin or to a modified human insulin, the amino terminus portion of which sequence does not define a cathepsin C dipeptide removal stop point. The compounds have the formula Met-Y-Protein in which Y is Tyr or Arg.
Claims10
A compound of the formula Met-Y-Protein in which Protein comprises three amino acid sequence units designated B, A, and X, in which B represents the B-chain of human insulin or a modified B-chain having one or more of the following amino acid modifications:
- (1) replacement of the Pro in position 28 by any of the following:
- Asp, Val, Leu, Ile, Nle, Arg, His, Lys, Phe, Ala, Gly, citrulline, and ornithine;
- (2) replacement of the Lys in position 29 by any of the following:
- L-Pro, D-Pro, D-hydroxyproline, L-hydroxyproline, L-(N-methyl)Lys, D-Lys, L-(N-methyl)Arg, and D-Arg;
- (3) replacement of the His in position 10 by Asp;
- (4) deletion of the Thr in position 30;
- A represents the A-chain of human insulin or a modified A-chain, in which the asparagine in position 21 is replaced by alanine;
- and X represents a moiety joined to the insulin A-chain or modified A-chain at the amino terminus of the A-chain and to the insulin B-chain or modified B-chain at the carboxy terminus of the B-chain, the amino terminus portion of which sequence does not define a cathepsin C dipeptide removal stop point, and Y is Tyr or Arg.
A compound of the formula
- Met-Y-Protein
- in which Y is Arg and Protein is human proinsulin in which Pro at position 28 of the B-chain is replaced with Lys and in which Lys at position 29 of the B-chain is replaced with Pro.
Dependencies are inferred from the claim text.