Insulin analogs which comprise A chain and B chain with disulfide bonds for use in treatment of diabetes and for cartilage regeneration

摘要

Insulin analogs (I) are new. Insulin analogs (I) comprising an A chain of formula (Ia) and a B chain of formula (Ib), with disulfide bonds between A-chain Cys 6>and A-chain Cys 11>, between A-chain Cys 7>and B-chain Cys 7>and between A-chain Cys 20>and B-chain Cys 19>, are new. A -1>A 0>A 1>Ile 2>Val 3>Glu 4>A 5>Cys 6>Cys 7>His 8>Ser 9>Ile 10>Cys 11>Ser 12>Leu 13>Tyr 14>A 15>Leu 16>Glu 17>A 18>Tyr 19>Cys 20>A 21>(Ia) B -1>B 0>B 1>Val 2>B 3>B 4>His 5>Leu 6>Cys 7>Gly 8>Ser 9>His 10>Leu 11>Val 12>Glu 13>Ala 14>Leu 15>Tyr 16>Leu 17>Val 18>Cys 19>Gly 20>Leu 21>Arg 22>Gly 23>Phe 24>Phe 25>Tyr 26>Thr 27>Pro 28>B 29>B 30>B 31>B 32>(Ib) A -1> : Lys, Arg or NH 2; A 0> : Lys, Arg or a bond; A 1> : Arg or Gly; A 5> : Asp, Glu or Gln; A 15> : Asp, Glu or Gln; A 18> : Asp, Glu or Asn; A 21> : Ala, Ser, Thr or Gly; B -1> : Asp, Glu or NH 2; B 0> : Asp, Glu or a bond; B 1> : Asp, Glu, Phe or a bond; B 3> : Asp, Glu or Asn; B 4> : Asp, Glu or Gln; B 29>= Arg, Lys, Phe, Ala, Thr, Ser, Val, Leu, Glu, Asp or a bond; B 30> : Thr or a bond; B 31> : Arg, Lys or a bond; B 32> : Arg-NH 2or Lys-NH 2; Independent claims are also included for: (1) producing (I) by producing a recombinant human insulin precursor, enzymatically processing the precursor to obtain two-chain insulin, and coupling this with arginamide in the presence of trypsin; (2) DNA coding for a precursor of (I) or for an A or B chain as above; (3) vector or host organism containing the DNA; (4) prepro insulin analog in which the C-peptide has N-terminal Arg and C-terminal Arg Arg, Arg Lys or Lys Arg Arg; (5) formulations comprising (I) in aqueous solution or in powder form or in suspension or comprising (I) and a chemical chaperone. ACTIVITY : Antidiabetic. MECHANISM OF ACTION : None given.