ESTER-BASED PEPTIDE PRODRUGS
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Abstract
Prodrug formulations of bioactive polypeptides are provided wherein the bioactive polypeptide has been modified by the linkage of a dipeptide to the bioactive polypeptide through an ester linkage. The prodrugs disclosed herein in some embodiments have extended half lives of at least 1.5 hours (e.g., at least 10 hours), and more typically greater than 20 hours and less than 70 hours, and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.
133 Citations
110 Claims
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1-85. -85. (canceled)
- 86. A prodrug comprising the general structure of Formula I:
- 91. A prodrug comprising a modified serine residue of the general structure of Formula III:
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94. A prodrug derivative of GLP-1 or glucagon comprising a polypeptide of the general structure of
R3—- Y—
R4wherein Y is a structure selected from the group consisting of - View Dependent Claims (95, 96, 97)
- Y—
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109. A complex comprising the general structure
A-B-Q; -
wherein Q is a bioactive peptide, polypeptide, or protein; A is an amino acid or a hydroxyl acid; B is an amino acid; and
A-B is a dipeptide that is linked to Q through formation of an ester bond between B and a hydroxyl group of Q, wherein the chemical cleavage half life (t1/2) of A-B from Q is at least about 1 hour to about 1 week in standard PBS solution under physiological conditions. - View Dependent Claims (110)
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Specification