Insulin like peptides

Abstract

It is described the preparation of Insulin like peptides, of chimeric Insulin like peptides and of their derivatives by the random combination of their chains A and their chains B and the pharmaceutical application of the obtained products.

1 . A method for manufacturing of peptides consisting of two different peptide chains, chain A and chain B ( FIG. 1 ) and of their derivatives in which the two chains are combined together
 i. With the reaction of a chain A which contains at least two disulfide bonds and of a B-chain which contains at least one disulfide bond in the presence of a reductive compound, preferably a thiol including chains A and B which contain free thiol groups.   ii. With the reaction of an A-chain which contains at least two disulfide bonds with a B chain which contains at least two cysteine residues in the presence of a mild oxidant, preferably DMSO, air or a hydrogen peroxide solution.   iii. With the reaction of a chain-A which contains at least one disulfide bond and at least two cysteine residues with free thiol groups with a B-chain which contains at least one disulfide bond in the presence of a mild oxidant, preferably DMSO, air or a hydrogen peroxide solution.   iv. With the reaction of a chain A which contains at least one disulfide bond and at least two cysteine residues with free thiol groups with a B chain which contains at least one disulfide bond in the presence of a mild oxidant, preferably DMSO, air or a hydrogen peroxide solution.   
     
     
         2 . A method according to  claim 1  for the production of peptides consisting from two different peptide chains, chain A and chain B, where the two chains are combined together under conditions suitable to form at least one intermolecular disulfide bond and where at least one of the chains A and B contain at least one additional intramolecular disulfide bond. 
     
     
         3 . A method according to  claims 1  and  2  where at least one of the chains A and B are A- or B-chains of an insulin like peptide. 
     
     
         4 . A method according to the  claims 1 - 3  where the chain of the insulin like peptide as those described in  FIG. 1  for the insulin-like peptides of human origin, is the whole chain, a chain fragment, a modified chain, chain of an insulin like peptide which has been extended by one or more natural and non-natural amino acids is of human or animal origin, chain A or chain B of insulin (INS), chain A or chain B of relaxin 1 (RLN1), chain A or chain B of relaxin 2 (RLN2), the region which corresponds to chain A or chain B of the insulin like growth factor 1 (IGF-1) and the region corresponding to chain A or B of the insulin like growth factor 2 (IGF-2). 
     
     
         5 . A method for producing chimeric peptides according to  claims 1 - 4  which includes the esterification of a derivative of a natural or non natural amino acid on a resin or on a linker of the trityl or benzhydryl-type and which is reacted sequentially with optionally protected residues of insulin-like peptides on solid phase. 
     
     
         6 . A synthetic insulin-like polypeptide as this is defined in any of the  claims 1 - 4  and is produced by the method described in  claim 1  and is pharmaceutically active, or is a pharmaceutically acceptable salt of it, a derivative and precursor of its pharmaceutical preparations. 
     
     
         7 . A polypeptide according to  claim 6  for the treatment of diseases associated with the production of collagen. 
     
     
         8 . A polypeptide according to  claim 6  for use in cardiac protection, in atherosclerosis and fibrosis of the heart, of the kidneys, of the arteries, of the liver and of the pancreas. 
     
     
         9 . A polypeptide according to  claim 6  for use in all types of eclampsia. 
     
     
         10 . A polypeptide according to  claim 6  for use against arthritis and pain of all types. 
     
     
         11 . A polypeptide according to  claim 6  for use against aging. 
     
     
         12 . A polypeptide according to  claim 6  for use in metabolic diseases such as diabetes of all types, and obesity. 
     
     
         13 . A polypeptide according to  claim 6  for use as a growth factor. 
     
     
         14 . A pharmaceutical formulation comprising a polypeptide as defined in any of  claims 6 - 13  and administered using a pharmaceutically acceptable carrier. 
     
     
         15 . A bicyclic polypeptide containing in its sequence 7-35 amino acids where at least 4 amino acids are cysteine residues which are joined together by two disulfide links and includes a typical sequence CysCys XYZ Cys where X, Y and Z are natural or non natural amino acids. 
     
     
         16 . A polypeptide according to  claim 15  belonging to the class of insulin-like peptides, to their smaller or larger parts or to their derivatives. 
     
     
         17 . The application of a polypeptide as described in  claims 15 - 16  for the manufacturing of peptides consisted of two peptide chains the chain A and the chain B which are connected together by at least one intermolecular disulfide bond and at least one of the two chains contains an additional intramolecular disulfide bond. 
     
     
         18 . A polypeptide as described in  claims 15 - 16 , which is administered as a pharmaceutical and react as described in  claim 17  in the human or the animal body with a non-properly folded (misfolded) protein or a mutant protein or aggregates of natural or modified proteins or plaques of aggregated proteins or protein oligomers of natural or non-natural proteins that are possibly precipitated in the human or animal body. 
     
     
         19 . A polypeptide according to  claims 15 - 16  for use in conformational diseases caused by misfolding of naturally occurring proteins such as aging, Alzheimer, Parkinson, diabetes and certain cancer types. 
     
     
         20 . A polypeptide according to  claims 15 - 16  that is used as an oxidase in the human or animal body or is used for the correct oxidation of biotechnologically produced proteins. 
     
     
         21 . A pharmaceutical formulation comprising a polypeptide as defined in any of the  claims 15 - 16  and is administered using a pharmaceutically acceptable carrier.