Fatty acid-acylated insulin analogs
AssigneeEli Lilly and Company
InventorDavid Benjamin Flora
Life of this patent
Estimating the term…
Abstract
Fatty acid-acylated insulin analogs are soluble at moderately acidic pH and provide long-acting basal control of glucose levels. In such a molecule, the insulin analog portion comprises an insulin A-chain, or an analog thereof, properly cross-linked to an analog of the insulin B-chain, wherein the ε-amino group of a Lys residue at either positions 28 or 29 of the B-chain analog is acylated with a fatty acid. The insulin analog portion of the molecules comprises an A-chain of insulin, or an analog thereof, with an optional Arg at position 0, properly cross-linked to a B-chain analog that includes Arg at positions 31 and 32.
Claims39
A fatty acid-acylated insulin analog comprising an insulin analog to which a fatty acyl chain is joined by an amide bond, wherein said fatty insulin analog has an isoelectric point that is higher than the isoelectric point of insulin.
A mono-acylated insulin analog, comprising:
- (a) a polypeptide of SEQ ID NO:1 properly crosslinked to a polypeptide of SEQ ID NO:2, or a pharmaceutically acceptable salt thereof, wherein the polypeptide of SEQ ID NO:1 has the sequence:
- 0 1 5 10 15 Xaa Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu (SEQ ID NO:1) 20 Glu Asn Tyr Cys Xaa
- wherein:
- Xaa at position 0 is either Arg or absent;
- and
- Xaa at position 21 is any naturally occurring amino acid except Cys and Lys;
- and
- the polypeptide of SEQ ID NO:2 has the sequence:
- 1 5 10 15 Phe Val Xaa Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr (SEQ ID NO:2) 20 25 30 Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Xaa Xaa Xaa Xaa Arg Arg
- wherein:
- Xaa at position 3 is any naturally occurring amino acid except Cys and Lys;
- Xaa at position 27 is either Thr or absent;
- Xaa at position 28 is selected from the group consisting of Pro, Leu, Val, Ala, Lys, and Asp;
- Xaa at position 29 is selected from the group consisting of Pro and Lys;
- Xaa at position 30 is absent or any naturally occurring amino acid except Cys or Lys;
- further wherein position 28 or position 29 is Lys, and
- if position 28 is Lys, position 29 is not Lys;
- and
- (b) Lys at position 28 or position 29 of SEQ ID NO:2 is acylated.
A human insulin analog selected from the group consisting of
- a B29-Nε-GlyA21ArgB31ArgB32-myristoyl human insulin analog,
- a B29-Nε-GlyA21GlnB3ArgB31ArgB32-myristoyl human insulin analog,
- a B29-Nε-ArgA0GlyA21ArgB31ArgB32-myristoyl human insulin analog,
- a B29-Nε-ArgA0GlyA21GlnB3ArgB31ArgB32-myristoyl human insulin analog,
- a B29-Nε-ArgA0GlyA21AspB3ArgB31ArgB32-myristoyl human insulin analog,
- a B29-Nε-ArgB31ArgB32-myristoyl human insulin analog,
- a B29-Nε-ArgA0ArgB31ArgB32-myristoyl human insulin analog,
- a B29-Nε-GlyA21ArgB31ArgB32-octanoyl human insulin analog,
- a B29-Nε-GlyA21GlnB3ArgB31ArgB32-octanoyl human insulin analog,
- a B29-Nε-ArgA0GlyA21ArgB31ArgB32-octanoyl human insulin analog,
- a B29-Nε-ArgA0GlyA21GlnB3ArgB31ArgB32-octanoy human insulin analog,
- a B29-Nε-ArgA0GlyA21AspB3ArgB31ArgB32-octanoyl human insulin analog,
- a B29-Nε-ArgB31ArgB32-octanoyl human insulin analog,
- a B29-Nε-ArgA0ArgB31ArgB32-octanoyl human insulin analog,
- a B28-Nε-GlyA21LysB28ProB29ArgB31ArgB32-myristoyl human insulin analog,
- a B28-Nε-GlyA21GlnB3LysB28ProB29ArgB31ArgB32-myristoyl human insulin analog,
- a B28-Nε-ArgA0GlyA21LysB28ProB29ArgB31ArgB32-myristoyl human insulin analog,
- a B28-Nε-ArgA0GlyA21GlnB3LysB28ProB29ArgB31ArgB32-myristoyl human insulin analog,
- a B28-Nε-ArgA0GlyA21AspB3LysB28ProB29ArgB31ArgB32-myristoyl human insulin analog,
- a B28-Nε-LysB28ProB29ArgB31ArgB32-myristoyl human insulin analog,
- a B28-Nε-ArgA0LysB28ProB29ArgB31ArgB32-myristoyl human insulin analog,
- a B28-Nε-GlyA21LysB28ProB29ArgB31ArgB32-octanoyl human insulin analog,
- a B28-Nε-GlyA21GlnB3LysB28ProB29ArgB31ArgB32-octanoyl human insulin analog,
- a B28-Nε-ArgA0GlyA21LysB28ProB29ArgB31ArgB32-octanoyl human insulin analog,
- a B28-Nε-ArgA0GlyA21GlnB3LysB28ProB29ArgB31ArgB32-octanoyl human insulin analog,
- a B28-Nε-ArgA0GlyA21AspB3LysB28ProB29ArgB31ArgB32-octanoyl human insulin analog,
- a B28-Nε-LysB28ProB29ArgB31ArgB32-octanoyl human insulin analog, and
- a B28-Nε-ArgA0LysB28ProB29ArgB31ArgB32-octanoyl human insulin analog.
Dependencies are inferred from the claim text.