Insulin analogs with enhanced zinc binding

An insulin analog or a physiologically tolerable salt thereof of the formula I

• in which
• (A1-A5) are the amino acids in positions A1 to A5 of the A chain of insulin;
• (A15-A19) are the amino acids in positions A15 to A19 of the A chain of insulin;
• (B8-B18) are the amino acids in positions B8 to B18 of the B chain of insulin;
• (B20-B29) are the amino acids in positions B20 to B29 of the B chain of
• R8 is choosen from Thr and Ala;
• R9 is choosen from Ser and Gly;
• R10 is chosen from Ile and Val;
• R14 is chosen from Tyr, His, Asp, and Glu;
• R21 is chosen from Asn, Asp, Gly, Ser, Thr, Ala, Glu, and Gln;
• R1 is chosen from any genetically encodable amino acid and a hydrogen atom, or is absent;
• R2 is chosen from Val, Ala, and Gly;
• R3 is chosen from Asn, His, Glu, and Asp;
• R4 is chosen from Ala, Ser, Thr, Asn, Asp, Gln, Gly, and Glu;
• R30 is chosen from any genetically encodable amino acid and —OH;
• Z is chosen from a hydrogen atom and a peptide having 1 to 4 genetically encodable amino acids, comprising 1 to 4 histidines (His);
• with the proviso that (1) when Z is a hydrogen atom, R1 or R3 is chosen from His, Glu, and Asp, and when R1 is a neutral or negatively charged amino acid, R3 is His;
• or (2) when Z is a hydrogen atom, R14 is chosen from His, Asp and Glu;
• and
• with the further proviso that when in formula I R3, R3 in combination with R21, or R3 in combination with R4, differ from human insulin, the insulin analog or the physiologically tolerable salt thereof of the formula I contains at least one additional variation from human insulin.