| 摘要 |
<p>Provided is an analog of glucagon having GIP agonist activity, with the following modifications: (a) a large, aromatic amino acid lacking an imidazole side chain at position 1, (b) a modification selected from the group consisting of: (i) a lactam bridge between the side chains of amino acids at positions i and i+4 or between the side chains of amino acids at positions j and j+3, wherein i is 12, 13, 16, 17, 20 or 24, and wherein j is 17, and (ii) one, two, three, or all of the amino acids at positions 16, 20, 21, and 24 of the analog are an ,-disubstituted amino acid, (c) amino acid modifications at one, two or all of positions 27, 28 and 29, and (d) 1-9 further amino acid modifications, wherein the analog exhibits at least 1% activity of native GIP at the GIP receptor, wherein the EC50 of the analog at the GIP receptor is less than 50-fold different from its EC50 at the GLP-1 receptor, optionally, wherein the GIP potency of the analog is within about 15-fold of the GLP-1 potency of the analog.</p> |
